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Cannabinoid receptor type 2: A possible target in SARS-CoV-2 (CoV-19) infection?



In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.
Int. J. Mol. Sci. 2020, 21, 3809; doi:10.3390/ijms21113809
Cannabinoid Receptor Type 2: A Possible Target in
SARS-CoV-2 (CoV-19) Infection?
Francesca Rossi 1,*, Chiara Tortora 1, Maura Argenziano 2, Alessandra Di Paola 2
and Francesca Punzo 1
1 Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi
Vanvitelli”, L. De Crecchio 4, 80138 Naples, Italy; (C.T.); (F.P.)
2 Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, S. Maria di
Costantinopoli 16, 80138 Naples, Italy; (M.A.); (A.D.P.)
* Correspondence:
Received: 24 April 2020; Accepted: 26 May 2020; Published: 27 May 2020
Abstract: In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan,
China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract
inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and
causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory
and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and
increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-
CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens,
as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated
by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and
immune response is well documented in fact in several settings. The stimulation of CB2 receptors is
known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards
the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal
stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in
COVID-19 pandemic emergency.
Keywords: SARS-CoV-2; cannabinoid receptor type 2; therapeutic strategies; molecular target;
immune response; inflammation; endocannabinoids system; COVID-19
1. Introduction
SARS-CoV-2 (CoV-19) is a sense RNA virus with envelope- and spike-like projections on its
surface [1]. It belongs to Coronavirinae family, whose genomes consist of about 30 kilobases, the
largest genomes known among RNA viruses. Two-thirds of their genome encodes viral
replicase/transcriptase functions that are involved in virus replication, while one-third encodes viral
structural proteins and accessory proteins. Coronaviruses can infect a wide range of vertebrates
including humans [2].
Prior to the outbreak of severe acute respiratory syndrome (SARS) in 2003, only two
coronaviruses (hCoV-229E and hCoV-OC43) were known to infect humans. Following 2003,
additional coronaviruses have been discovered in humans: SARS-CoV, hCoV-NL63, hCoV-HKU1,
Middle East respiratory syndrome coronavirus (MERS-CoV), and the new SARS-CoV-2. SARS-CoV,
MERS-CoV and SARS-CoV-2 are highly pathogenic in humans and cause severe acute respiratory
distress with a high rate of mortality. Remarkably, all three viruses are believed to have originated
from bats [3]. The latter, SARS-CoV-2, emerged in late December 2019 as responsible for a severe
Int. J. Mol. Sci. 2020, 21, 3809 2 of 16
acute respiratory syndrome named COronaVIrus Disease (COVID-19), in Wuhan, Hubei province,
China and rapidly outbroken into a major global pandemic [4–6]. It has been proved to have stronger
infectivity but less virulence compared to SARS and MERS [7].
COVID-19 can manifest with a variety of symptoms from mild to severe (flu, fever, cough,
fatigue, shortness of breath, infection of the lower respiratory tract, pneumonia, fibrosis with
thrombosis in pulmonary small vessels, etc.) and even death (≈3.4%). It can also lead to complications
associated with the immune response being out of control, such as disseminated intravascular
coagulation (DIC) [8]. The severity of the disease depends on the efficiency of the affected individuals’
immune system and the presence of co-morbidities [9–12]. A common feature is the strong
inflammatory response, which manifests through elevated C-reactive protein (CRP), pro-
inflammatory cytokines production (Il-6, IL-10, IL-1), higher TNF-α, neutrophil count, D-dimer and
blood urea [13]. SARS-CoV-2 spreads in the population at a rate of 0.8%–3% more than the normal
flu and binds to angiotensin-converting enzyme 2 (ACE2) with high affinity to infect humans [14]. It
mostly affects the elderly and people with chronic underlying diseases and it shows a preference for
men [15], for reasons that we will discuss later.
At present, the only supporting treatments of CoV-19 flu are those aimed at the side effects
caused by the virus—such as inflammation and pulmonary fibrosis, recognized as the first causes of
death—symptomatic and respiratory support (oxygen therapy and extracorporeal membrane
oxygenation) [9]. In some critical circumstances, convalescent plasma and immunoglobulin G have
been administered to patients [16]. Several antiviral drugs and systemic corticosteroid treatment
commonly used against influenza viruses are inefficient to treat COVID-19 [17]. Combinations of
antiviral drugs, immunomodulatory, anti-parasite and common flu remedies have been tried with
some results [18], but to date, scientists all over the world are working intensively on the therapies
and vaccines against the virus.
As already mentioned, the spikes proteins of Coronavirus bind to ACE2 receptors, fusing to the
cell membrane and releasing the viral RNA into the host cells. The viral RNAs are detected by Toll-
like receptors (TLR) 3, TLR7, TLR8 and TLR9. Hence, virus–cell interactions produce a diverse set of
immune mediators against the virus. Viral replication in host cells is always associated with
inflammation and immune activation [19].
The immune system has complex mechanisms to fulfill its function and respond to a variety of
signaling molecules including hormones, neurotransmitters, and specific lipids, such as
endocannabinoids (eCBs) [20]. The biological effects of cannabinoids are mediated through the
activation of G-protein-coupled cannabinoid (CB) receptors [21]. The endocannabinoid system (ECS)
includes the cannabinoid receptor type 1 (CB1) and 2 (CB2), the endogenous cannabinoids, and the
enzymes for their metabolism. CB1 is mostly expressed in the central nervous system and is strongly
associated with the psychoactive effects of cannabinoids [22]. CB1 is also expressed at low levels in
peripheral tissues [23]. Instead, CB2 is highly expressed by immune cells (B cells, natural killer cells,
monocytes, neutrophils, CD8 lymphocytes, CD4 lymphocytes) [24,25] and in several organs and
tissues such as liver, spleen, nasal epithelium, thymus, brain, lung and kidney [26–28]. Both CB1 and
CB2 receptors have been widely demonstrated to be important modulators of the immune system,
potentially inducing immunosuppression [29]. CB2 is widely known for its immunomodulatory role,
which is related to four events: i) induction of apoptosis, ii) suppression of cell proliferation, iii)
inhibition of proinflammatory cytokines production and increase in anti-inflammatory cytokines and
iv) induction of regulatory T cells [30]. It is therefore conceivable that, also in COVID-19, the
activation of the ECS plays a role in preventing and/or influencing the development and the severity
of the disease.
D9-Tetrahydrocannabinol (D9-THC) and cannabidiol (CBD) are the phytocannabinoids that
have been studied the most for their medicinal properties, due to their ability to suppress lymphocyte
proliferation and inflammatory cytokine production [31–33]. However, they bind to both CB
receptors; thus, considering that CB1 receptors are localized predominantly in the central nervous
system, psychotropic effects have been often observed following their administration [23–26].
Int. J. Mol. Sci. 2020, 21, 3809 3 of 16
The specific activation of CB2 receptors induces apoptosis, inhibits the production of
autoantibodies, pro-inflammatory cytokine expression, matrix metalloproteinases and bone erosion
and induces a shift from a Th1 to Th2 immune response and induced myeloid-derived suppressor
and T-regulatory cells [34]. In addition, CB2 receptor exerts an inhibitory effect on inflammatory
processes [29], including macrophage migration [35], and provides an important therapeutic target
for reducing some immune-pathological processes associated with viral infections [31–33].
Therefore, given the well-known involvement of CB2 receptors in immunomodulatory
processes and the recent knowledge about the inflammatory, coagulative and cytokines misbalance
that COVID-19 patients have to face, we describe the possible role of the CB2 receptor in modulating
them, suggesting it as possible therapeutic target in COVID-19.
2. CB2 and Viral Infections
The immune system acts through complex mechanisms to accomplish its defensive function.
Cells participating in the immune response bear cannabinoid receptors and in particular cannabinoid
receptors type 2 [29]. Therefore, the activation of these receptors might have a decisive role in
preventing and modulating the development of an infective disease. CB2 receptors are locally
overexpressed in the presence of viral infection, and their activation through a selective agonist
inhibits the leukocytes migration into the site of inflammation [36].
Many studies have examined the effect of cannabinoids on resistance to infections. Δ9-THC
treatment seems to sensitize to several microbial infections [37], such as herpes simplex virus type 2,
since Δ9-THC suppresses host defenses and, as well as the CB2 selective agonists, has suppressive
effects on B-cells, monocyte/macrophages and dendritic cells. It is important to underline that
compounds interfering with inflammatory processes could either compromise or improve the host
response to viral infection because there are some viruses that benefit from host inflammation and
other ones that are eradicated by host inflammation [38,39]. Agonists of CB2, but not CB1, have been
shown to reduce infection in primary CD4+ T cells following cell-free and cell-to-cell transmission of
CXCR4-tropic virus. CB2 agonist have been shown to decrease CXCR4-activation-mediated G-
protein activity and MAPK phosphorylation, alter the cytoskeletal architecture of resting CD4+ T and
impair productive infection following cell-free or cell-associated viral acquisition of CXCR4-tropic
HIV-1 in resting cells. Thus, indicating that the clinical use of CB2 receptor agonists in the treatment
of AIDS symptoms may also exert beneficial adjunctive antiviral effects against CXCR4-tropic viruses
in late stages of HIV-1 infection [32]. CB2 stimulation also reduces some effects of inflammatory
processes in HIV-infected patients [36]. HIV infection causes changes in CB2 receptor expression, as
it has been observed during the process of in vitro monocyte differentiation into macrophages [40].
CB2 increases as HIV infection progresses, and on infected macrophages, the exposure to CB2
receptors selective agonist JWH133 resulted in a dose-dependent decrease of reverse transcriptase
activity/viral replication activity [41].
Moreover, acute viral respiratory infections could be responsible for the onset of secondary
bacterial super-infections, which cause a significant worsening of clinical course. The bacterial super-
infection is caused by bacterial colonization of respiratory tracts damaged by the viral infection and,
consequently, alteration of host immune responses [42]. SARS-CoV-2, in some cases, caused
secondary bacterial infection, which worsened the prognosis [43]. Sepsis consists in both pro-
inflammatory and immunosuppressive responses to an infection, which can induce multiple organ
failure and death. The role of CB2 receptors in sepsis has been evaluated by Tschöp et al., who
demonstrated that CB2 stimulation plays a key role in neutrophils. Its stimulation in fact reduced
neutrophils number, decreasing mortality and tissue damage. A reduced neutrophil recruitment
during sepsis is associated with increased survival. Moreover, neutrophils can kill bacteria and
reduce tissue injury [44]. Therefore, the use of CB2 selective agonists could be suggested to regulate
neutrophil recruitment and bacterial clearance. A variant of the CB2 receptor at codon 63 of the CB2
gene leads to the substitution of glutamine (Gln (Q)) with arginine (Arg (R)), with a consequent
difference in protein polarization. These variants affect the response of CB2 receptor to cannabinoids.
The receptor carrying R showed a reduced immune modulation function when activated by
Int. J. Mol. Sci. 2020, 21, 3809 4 of 16
cannabinoids, therefore influencing the acquisition, the severity and the duration of the infection
from other RNA viruses [45,46]. Cannabinoids may also induce less damage to endothelial barriers,
thanks to their influence on several pro-inflammatory events [47]. We found that in HIV/HCV-
coinfected patients, in T cells from QQ subjects, CB2 stimulation mediates the inhibition of their
proliferation, while in subjects with the RR haplotype, T cells proliferation is reduced, indicating that
the CB2-63RR variant is associated with weaker and transient inhibition of T cells compared to the
CB2-63QQ. The CB2 RR variant has been also indicated as a prognosis worsener of liver
necroinflammation in HIV/HCV-coinfected patients, while when it is caused by HCV monoinfection,
the CB2 QQ variant is associated with more severe liver necroinflammation [48].
CB2 receptors activation has also been studied in children with viral respiratory infection using
a selective agonist, JWH133. The CB2 Q63R variation was associated with a more severe clinical
course of the acute viral infection and increased risk of hospitalization. Children infected with
Respiratory Syncytial Virus carrying the QQ genotype showed the associated risk of developing
severe respiratory complications increased more than two-fold. CB2 receptors activation by JWH133
reduced the cytokines production and limited lung pathology [41]. Collectively, CB2 receptor is
associated with Respiratory Syncytial Virus infection severity during infancy, and it has been
suggested as a therapeutic target to alleviate virus-associated immunopathology. Null mice for
cannabinoid receptors show a greater inflammatory response to influenza infection, strongly
suggesting that cannabinoid receptors have a role in immuneregulation [49,50].
Taken together, all those studies confirm that CB2 receptors have a central role in immune
balance and negatively regulate the immune response magnitude. The immune system fights foreign
agents, and the activation of CB2 receptors triggers anti-inflammatory action; therefore, targeting
these receptors may be a novel and effective approach for the treatment of COVID-19.
3. SARS-CoV-2 and CB2 in Inflammation: Cytokines, Macrophages, Mesenchymal Stromal Cells
3.1. Inflammation and Cytokines Production
Among the clinical features of COVID-19 patients, there is a very high number of circulating
inflammatory molecules, including C reactive protein (CRP) and pro-inflammatory cytokines [51]. In
recent weeks, several authors observed and confirmed this alteration [52,53]; in particular, Huang et
al. [54] measured cytokine levels in 41 patients reporting the increase of IL-1β, IL-7, IL-8, IL-9, IL-10,
fibroblast growth factor (FGF), granulocyte-macrophage colony stimulating factor (GM-CSF), IFNγ,
granulocyte-colony-stimulating factor (G-CSF), macrophage inflammatory protein 1 alpha (MIP1A),
tumor necrosis factor (TNFα) and vascular endothelial growth factor (VEGF). The pro-inflammatory
cytokine IL-6 seems to be critically high in severe COVID-19 patients. The altered cytokine profile
observed in COVID-19 patients is very similar to the Cytokine Storm (CS) that characterizes SARS
(severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), other two kinds
of pneumonia caused by a coronavirus [55].
In the above-cited syndromes, CS and inflammatory cell infiltration in the lungs lead to severe
injury, acute respiratory distress and death. Given the presence of CS also in COVID-19 patients, an
anti-inflammatory therapy with non-steroidal anti-inflammatory drugs, glucocorticoids, cytokines
antagonists, monoclonal antibodies (i.e., Tocilizumab, Anakinra, Idroxiclorochin, and others) or JAK
inhibitors so far have proven to be helpful. On the other hand, the use of anti-inflammatory drugs
could present some limits. First of all, cytokine inhibitors are available and specific only for a few of
the cytokines actually involved in inflammatory cascade. About the use of corticosteroids, further
investigations are needed; their capability to reduce both inflammation and immune response could
be beneficial as well as could delay the elimination of the virus. But controversial hypotheses are
present in literature regarding this issue. Chen Wang et al. [54] reported clinical evidence about SARS
[56] and MERS [57], in which the administration of corticosteroids did not induce any difference in
terms of mortality, but it was only associated with a worst clearance of viral RNA from the respiratory
system. Moreover, therapies reducing immune response (such corticosteroids above mentioned)
could increase the risk of new infection as well as fuel existing infections [58]. Indeed, patients treated
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with immunosuppressants are immunocompromised and therefore exposed to high hazard of
mortality [59]. Puja Mehta et al. suggested, in fact, screening severe COVID-19 patients for
hyperinflammation (considering ferritin levels, platelet count, erythrocyte sedimentation rate, etc.)
to identify individuals in which immunosuppression could be fatal [60].
Therefore, there are yet discordant opinions about the most suitable treatment. In a multicenter
study on 150 COVID-19 patients in Wuhan, Ruan Q. et al. showed that in addition to the
overproduction of inflammatory cytokines, especially of IL-6, there is also an increase in ferritin levels
[61]. These data suggest a virus-dependent hyperinflammation in which the immunosuppressive
effect of anti-inflammatory drugs could be beneficial instead. In 2016, Shakoory B. et al. highlighted
this effect of the IL-1R antagonist (Anakinra) in reducing mortality in patients with macrophage
activation syndrome [62]. These authors then suggest screening the severe COVID-19 patients for
hyperinflammation and identify those who could benefit from the immunosuppressive effect of anti-
inflammatory therapy.
The role of the endocannabinoid system in modulating inflammation is well known, and in
particular, in cytokine release. In the literature, it is reported that AEA, an endogenous agonist with
high affinity to CB1, reduces the production of pro-inflammatory IL-6 [63], and it is known that THC,
a CB1 and CB2 receptor partial agonist inhibits the release of IL-12 and IFN-γ [64]. Moreover, in 2014,
Sardinha et al. demonstrated in vivo that the inhibition of MAGL and FAAH, the enzymes that
respectively degrade 2-AG and AEA, has CB2-mediated anti-inflammatory effects [65]. Also (E)-β-
caryophyllene ((E)-BCP) is a phytocannabinoid that selectively binds to the CB2 receptor, and it is a
functional CB2 agonist. (E)-BCP inhibits lipopolysaccharide (LPS)-induced proinflammatory
cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2
phosphorylation in monocytes. Furthermore, (E)-BCP administration strongly reduces the
inflammatory response in wild-type mice but not in mice lacking CB2 receptors, providing evidence
that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a
functional non-psychoactive CB2 receptor ligand and as an anti-inflammatory cannabinoid. (E)-BCP
has effects also on vascular inflammation and significantly ameliorated vascular oxidative stress
Furthermore, there are several pieces of evidence about the specific involvement of CB2 receptor
in modulating inflammation in different pathologies. To begin, in 2015, Verty AN et al. [68] observed
that JWH-015, a CB2 receptor agonist, reduced obesity-associated inflammation in mice. The next
year, 501 Italian obese children were genotyped for the CB2 Q63R variant, a less functional variant of
CB2, highlighting that this variant was associated with high levels of pro-inflammatory IL-6 similar
to the levels observed after blocking CB2 receptor in lean-derived adipocytes in vitro [69]. This and
many other alterations seem to contribute to the low-grade inflammation of white adipose tissue in
obese people [70]. The same CB2 Q63R variant was associated also with liver necroinflammation in
chronic hepatitis patients with HIV/HCV coinfection [48], synovium inflammation in juvenile
idiopathic arthritis [71], liver damage in children with non-alcoholic fatty liver disease [72] and
inflammation of gastro-intestinal tract in inflammatory bowel disease (Crohn’s disease and ulcerative
colitis) [73] and in celiac disease [74]. Moreover, it has been demonstrated that the cannabinoid CBD
inhibits the production of the pro-inflammatory cytokines IL-6, IL-8 and TNF-α in in vitro models of
allergic contact dermatitis [75], and in osteoarthritis, THC reduced TNF-α, IL-1, IL-6 and IL-8 release
in LPS-stimulated MG63 cells, demonstrating the anti-inflammatory CB2-mediated role [76].
Immune thrombocytopenia (ITP) is another disease characterized by abnormal cytokine
secretion and influenced by the presence of the CB2 Q63R variant. In particular, mesenchymal stem
cells from ITP patients overproduce the pro-inflammatory cytokine IL-6. Regular levels are restored
using JWH-133, a selective agonist at CB2 receptors [77]. A proper activation of CB2 receptor reduces
the levels of several inflammatory mediators (IL-6, IL-1β and TNF-α) also in animal model of multiple
sclerosis [78].
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3.2. Inflammation and Macrophages
The importance of macrophages’ role in SARS-CoV-2 infection has been assessed by
demonstrating a crosstalk between macrophages and the ACE2-expressing cells in lung, liver and
stomach. Macrophages are recruited by CoV-targeted cells during inflammation, and they play a
defensive or destructive role in infection [79]. In particular, it has been demonstrated that in lungs of
COVID-19 patients with diffused alveolar damages, the cell infiltration consists mainly of
macrophages and monocytes, moderate mononuclear giant cells and very few lymphocytes. After
virus infection, those cells are responsible for the “primary cytokine” storm mentioned above [55].
The presence of inflammatory cells infiltration is responsible for acute lung injury, causing acute
respiratory distress syndrome and death [80].
Macrophages are mononuclear phagocytes with a key role in inflammatory response, cytokines
production, phagocytosis, cellular proliferation and tissue restoration in wounds. They are
characterized by a remarkable plasticity, showing two different activation phenotypes based on the
microenvironment in which they lay [81]: classically activated macrophages (M1) and alternative
activated macrophages (M2). M1 macrophages are activated after interferon-gamma (INF-γ) and
lipopolysaccharide (LPS) stimulation. They exhibit pro-inflammatory and anti-tumor properties by
releasing various types of pro-inflammatory cytokines and chemochines, such as Tumor Necrosis
Factor (TNFα), Interleukin-6 (IL-6), Interleukin-1 Beta (IL-1β) and Nitric Oxide Synthase (INOs). On
the other hand, M2 polarization is promoted both by Phosphatidylinositol 3-kinase-AKT-mammalian
target of rapamycin (PI3K-Akt-mTOR) signaling pathway and by the anti-inflammatory cytokines
Interleukin-4 (IL-4) and Interleukin-10 (IL-10); they perform anti-inflammatory and
immunosuppressive effects by releasing anti-inflammatory cytokines (IL-10) and promote tumor
progression. An imbalance of M1/M2 is responsible of inflammation [81–83].
It is known that CB2 receptors are mainly expressed in peripheral immune cells, including
macrophages [20]. Several studies have demonstrated a role for this receptor as a mediator of anti-
inflammatory and immunosuppressive properties. It inhibits immune cell activation and pro-
inflammatory mediator release (cytokines, reactive oxygen species (ROS), nitric oxide, etc.). Thus, it
has been suggested as a possible target for treatment of inflammatory and autoimmune diseases,
such as inflammatory bowel disease, juvenile idiopathic arthritis, inflammatory bowel disease, celiac
disease, obesity and neuroinflammatory diseases [84,85]. All these pathologies are characterized by
an alteration of immune cell activation and an increase of pro-inflammatory cytokines release.
Moreover, it has been shown that CB2 receptor stimulation with its selective agonists reversed
these pathological conditions by reducing both B and T lymphocyte [86], by promoting mesenchymal
stromal cells’ (MSCs) homing and immunosuppressive and anti-inflammatory activities [77,87] and
by limiting pro-inflammatory cytokine release in macrophages, inhibiting M1 polarization [83].
Several studies have highlighted the importance of the role of CB2 receptors as regulators of
macrophage polarization in inflammatory processes. In particular, it has been shown that its
stimulation with selective agonists induced a reduction of the pro-inflammatory macrophage
population (M1) and an increase of the anti-inflammatory phenotype (M2) [88]. Du et al. have
demonstrated that stimulation of CB2 receptor with its selective agonist JWH-133 attenuated
inflammation during skin wound healing by inhibiting M1 macrophages rather than by activating
M2 macrophages in skin lesion. They showed a significant reduction of M1 markers and pro-
inflammatory cytokines, CD86, iNOS, IL-6 and IL-12, after treatment with JWH133 or GP1a. These
results indicated that CB2 inhibited the release of pro-inflammatory cytokines, preventing the
macrophages polarization to the M1 phenotype [83].
Also in neuroinflammation, CB2 receptor stimulation exerts its anti-inflammatory effects,
modulating macrophage polarization. Braun et al. demonstrated that, in patients with
neuroinflammation induced by traumatic brain injury, stimulation of CB2 receptor with its selective
agonist, GP1a, induced M2 anti-inflammatory macrophage polarization and inhibited M1 pro-
inflammatory polarization, determining a reduction of pro-inflammatory mediator expression
(TNFα, IL1β, IL6, CCl2, CXCL10 and iNOS) and an increase of anti-inflammatory mediator
expression (IL10, ArgI) [88].
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CB2 receptor displays its anti-inflammatory properties also in alcoholic liver disease, by acting
on Kupffer cells polarization. Louvet et al. proposed CB2 receptors as a novel regulator of Kupffer
cell polarization. Their in vivo and in vitro experiments showed an increase of M1 phenotype markers
and a reduction of the M2 phenotype markers in response to chronic alcohol feeding after genetic
deletion of CB2. Instead, after JWH-133 treatment, they observed an inhibition of pro-inflammatory
M1 profile by shifting the M1/M2 balance toward a predominant alternative M2 response, and a
reduction of inflammation [26]. Moreover, human lung-resident macrophages express CB2 receptor,
and its stimulation induces a reduction in the release of some pro-inflammatory cytokines (such as
IL-6) and angiogenic factors [89].
3.3. Mesenchymal Stromal Cells (MSCs) in Inflammation
In COVID-19 patients, an alteration in cytokine production is present that is very similar to the
process called cytokine storm, characterized also by an overproduction of immune cells [59].
Considering the well-known anti-inflammatory function of mesenchymal stromal cells (MSCs)
[90,91], in the last few months, several authors investigated the possibility to use MSCs to treat
COVID-19 patients. In particular, these cells seem to reduce the secretion of inflammatory factors,
thus improving lung function after acute injury caused, for example, by influenza virus. Jiajia Chen
et al. [92] performed a clinical study in which they tested menstrual-blood-derived MSCs in patients
with acute respiratory distress syndrome (ARDS) caused by H7N9 infection and observed benefits in
the most severe cases.
H7N9 is a subtype of influenza A viruses with symptoms very similar to COVID-19 (cough,
fever, shortness of breath, etc.) and with similar complications (ARDS and lung failure) [93,94].
Hence, the authors suggested that a therapeutic strategy used to manage H7N9 inflammatory
damages could be used also in ARDS-induced severe pneumonia of COVID-19 patients. In detail,
MSCs have the capability to increase the number of peripheral lymphocytes and at the same time to
reduce the cytokine-secreting immune cells (CD4+ T cells, CD8+ T cells and NK cells) in the
circulating blood [95,96] without any adverse reaction [97]. This immunomodulatory effect is due to
their interaction with immune cells, directly or mediated by paracrine cytokines [98,99]. Beyond the
great influence that MSCs exert on immune response, it has also been observed that they produce a
specific molecule, the leukemia inhibitor factor (LIF), useful in counteracting the cytokine storm in
viral pneumonia [100]. The LIF amount produced by MSCs is not enough, but in literature is reported
the use of synthetic stem cells (LIF-Nano) with a 1000-fold greater potency in producing LIF and able
to reverse paralysis in preclinical model of multiple sclerosis within 4 days [101].
From our previous studies, we know that MSCs abundantly express CB2 receptors and that this
feature, together with the above-described characteristics, makes them suitable in managing CoV-19
infection. It has been observed that the selective stimulation of MSCs with agonists at CB2 receptor,
JWH-133, improved their survival and their immunomodulating properties with important impact
in regulating lymphocytes activity and cytokine secretion [77]. On these bases, MSCs therapy,
together with a proper stimulation of their CB2 receptor, could be proposed to improve COVID-19
patients’ conditions with a double function: to repair tissue damages on stem cells and to drive
immune response in a protective direction immunomodulating cells. MSCs are easy to access and
isolate from different sources (umbilical cord, dental pulp, menstrual blood, etc.), and they can be
stored for repetitive therapeutic usage with absolute effectiveness [102–104]. Moreover, with RNA-
sequencing, it has been observed that MSCs are negative for ACE2 and TMPRSS2 [105], the main
proteins involved in COVID-19 pathogenesis; therefore, these cells can be safely infused in affected
patients without being infected by CoV-19 rather bringing all the above-mentioned beneficial effects
to the host [106] (Figure 1).
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Figure 1. Inflammatory response in lung after coronavirus (SARS-CoV-2) infection. Lung
susceptibility to SARS-CoV-2 infection depends on viral spike proteins specificity for angiotensin-
converting enzyme 2 (ACE2) receptors on alveolar epithelial cells. This interaction leads to
hyperinflammation sustained by cytokine storm, increase of pro-inflammatory M1 macrophages and
T-helper cells, all associated in a vicious circle in which each event enhances the alteration of the other
ones. The selective stimulation of Cannabinoid Receptor type 2 (CB2) receptors on macrophages, T-
helper cells and mesenchymal stromal cells (MSCs) could be proposed to contain the inflammatory
state in COVID-19 patients.
4. CB2 and Estrogens
Several epidemiological studies suggest sex-specific differences in the incidence of CoV-
19/SARS-CoV-2, with men more susceptible to infection (about 70% of infected patients) than women
[15,52,54]. Interestingly, this difference has already been observed in the past for other viral infections
such as severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome
(MERS)-CoV [107,108]. In effect, it is already widely known that males and females react differently
to RNA virus infections [64]. In general, males respond with a less strong immune response [109].
Women are less susceptible to viral infections for various reasons related to a different innate
immunity, sex chromosomes [110] and especially steroid hormones [111]. Female hormones seem to
confer a natural resistance against many diseases. At high concentrations, estrogens have an immune-
suppressive effect and at low concentrations exhibit an important immune-stimulatory activity [112].
Steroid hormones exert their effects through intracellular receptors that can regulate the expression
of target genes by binding to specific enhancer elements [113]. The role of estrogens in modulating
cannabinoid receptor expression and endocannabinoids levels is widely known, both in physiological
and in pathological conditions [114–116]. Studies have demonstrated that 17β-estradiol increases the
expression of CB2 receptors in osteoclasts in vitro through the recruitment of an estrogen-responsive
element in the CB2 gene [117]. In addition, selective estrogens receptor modulators (raloxifene,
bazedoxifene and lasofoxifene) act as CB2 receptors agonists [118,119]. Estrogens and cannabinoids
share several molecular pathways and involvement in several inflammatory processes [120]. Peretz
et al. demonstrated a role of estrogens in inhibiting influenza A virus replication in nasal epithelial
cells derived from humans [121]. Accordingly, Channappanavar et al. showed a protective effect of
estrogen signaling in mice infected with SARS-CoV-1, demonstrating that the ovariectomy or
pharmacological antagonism of estrogen receptor in female mice increases mortality [122]. Moreover,
they observed a large number of macrophages and an increased level of pro-inflammatory cytokines
in the lungs of SARS-CoV1–infected ovariectomized mice compared with control female mice,
Int. J. Mol. Sci. 2020, 21, 3809 9 of 16
suggesting that estrogen signaling is able to suppress macrophage activity in the lungs, probably
through the NF-κB inhibition and the subsequent pro-inflammatory cytokine production [122].
Considering that the CB2 receptor regulates the immune system and inhibits inflammation in many
inflammatory disease [85], it is conceivable that the protective effects of estrogens could strongly be
related to a CB2 receptor activation. In a model of lung injury, CB2 receptor up-regulation inhibits
NF-κβ activity, reducing pro-inflammatory factors release (TNF-α, IL-12 and IL-6) and increasing
anti-inflammatory factors (IL-10 and IL-4) production [123], confirming that CB2 receptors activation
may act as a novel immunomodulatory strategy to alleviate lung diseases through the inhibition of
immune cells.
5. Conclusions
We have discussed the clinical features of SARS-CoV-2 infection, including the severe acute
inflammation that causes cytokine storm in COVID-19 patients.CB2 receptors stimulation is known
to exert anti-inflammatory and immunomodulating effects by reducing the release of pro-
inflammatory cytokines, by shifting the M1/M2 ratio towards the anti-inflammatory M2 macrophage
phenotype and by improving the MSCs-repairing properties. It is also well documented that human
lungs, macrophages and MSCs, express CB2 receptors. Estrogens exert a protective effect in COVID-
19, which explains sex-specific differences observed in SARS-CoV-2 infection. This could also be
related to a CB2 activation. We suggest therefore, the possibility of using CB2 as a pharmacological
target for the treatment of SARS-CoV-2 infection.
We hypothesize that the selective stimulation of CB2 could reduce the inflammatory response
in SARS-CoV-2 patients and could improve the outcome. The stimulation of CB2 could control the
inflammatory cascade in several checkpoints, considering its capability to reduce the production of a
large number of cytokines, contrarily to the extremely selective action of monoclonal antibodies
directed against a specific interleukin. On the other hand, CB2 receptor stimulation has a well-
documented immunosuppressive effect by reducing immune cells proliferation [124] and production
of antibodies [125]; thus, it could be greatly beneficial in containing the exacerbated inflammatory
response in COVID-19 patients.
To date, there are no commercially available agonists, approved for the use in human subjects,
that specifically bind to CB2 receptors. HU910, HU308 and JWH133 have high specificity to CB2
receptors and are recommended to study the role of this receptor in biological processes and diseases
[126]. Cannabidiol (CBD) is also involved in modulation of inflammatory processes through a CB2-
dependent mechanism. It induces CB2 activation indirectly, by increasing AEA levels, and exerts its
anti-inflammatory properties by reducing pro-inflammatory cytokines release in experimental model
of allergic contact dermatitis [127]. A novel ∆9-tetrahydrocannabinol (∆9-THCP) binds with high
affinity to both human CB1 and CB2 receptors. In particular, the affinity shown for CB1 is thirty-fold
higher compared to the one reported for Δ9-THC in the literature, and it was 5 to 10 times more active
on the CB2 receptor. It has also been demonstrated that Δ9-THCP showed a cannabimimetic activity
several times higher than its pentyl homolog Δ9-THC, also at lower doses [127]. Nevertheless, more
studies are necessary to develop a commercially available CB2 selective agonist, and clinical studies
with the available phytocannabinoids should be encouraged.
Another interesting field of investigation could be the screening of COVID-19 patients for CB2
Q63R. In this way, it would be possible to clarify if, also in this case, the variant is a predisposing
factor to the infection and also if it is associated with the appearance of the most severe side effects
(respiratory distress, pulmonary fibrosis and death). All these actions could produce better
knowledge on SARS-CoV-2 pathogenesis and significantly improve the management of COVID-19
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interests.
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... Cannabinoid receptor type 2: a possible target in SARS-CoV-2 (CoV- 19) infection ? (34 ) 2020 Italy Opinion article Objective: To assess whether the CB2 receptor can be a therapeutic target in the COVID-19 pandemic emergency. ...
... On the other hand, researches (16,(20)(21)(30)(31)(32)(33)(34)(35) addressed the possibility of using exogenous CB, especially CBD and THC, in the prophylaxis and treatment of COVID-19 through the suppression of immune activation, with an anti -inflammatory and reduced expression of ACE2 in coronavirus target tissues. A study (36) highlights the risk of drug interactions of THC and/or CBD with anti-inflammatory drugs used in the treatment of infection caused by SARS-CoV-2. ...
... There was little evidence addressing the use of exogenous CB for therapeutic purposes during and after the individual contracted COVID-19, but with positive indications for the immunomodulatory effect through the activation and inhibition of cytokines (16,(20)(21)28,(30)(31)(32)(33)(34)(35) . Therefore, it is necessary to develop further research that explores this use, especially in individuals with coronavirus infection. ...
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Objective: to identify and synthesize studies on the effects of cannabis use and its relation with SARS-CoV-2, as well as the therapeutic possibilities of using cannabinoids in the prevention and treatment of COVID-19. Methods: scoping review, in the BVS, PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, CAPES and ProQuest databases, with no language restriction and year limitation. Narrative synthesis was performed. Results: cannabis use causes changes in the respiratory and vascular system, it reduces the production of cytokines, which affects the users' immune system, increasing the susceptibility to infection and progression of COVID-19. However, studies have suggested the use of cannabinoids in the prophylaxis and treatment of COVID-19, due to their anti-inflammatory effect. Conclusions: the use of inhaled cannabis increases the progression and severity of the infection. On the other hand, the benefits of cannabinoids seem promising to modulate the immune system, but it needs further studies.
... A few structural clusters, such as 4-quinolones, 4-hydroxy-2-quinolones and indoles, can be identified in the library, which represent privileged medicinal chemistry scaffolds [18]. Interestingly, a large number of molecules within this library belong to the family of cannabinoid receptor 2 ligands, which have recently been proposed as a therapeutic option for SARS-CoV-2 infections for their ability to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells [19]. This aspect is particularly relevant because it could, in principle, allow us to combine virus inhibition at multiple targets with the treatment of the effects of virus infection that are mainly inflammatory and coagulative. ...
... To define the potential binding pose of ligands on the S-glycoprotein, we performed a docking simulation in the binding region proposed by Bongini P. et al. [19]. In the virtual screening results, the compounds COR480, COR482 and COR483 exhibited the lowest binding free energy on the target (−8.8 ...
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Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease that spreads rapidly in humans. In March 2020, the World Health Organization (WHO) declared a COVID-19 pandemic. Identifying a multi-target-directed ligand approach would open up new opportunities for drug discovery to combat COVID-19. The aim of this work was to perform a virtual screening of an exclusive chemical library of about 1700 molecules containing both pharmacologically active compounds and synthetic intermediates to propose potential protein inhibitors for use against SARS-CoV-2. In silico analysis showed that our compounds triggered an interaction network with key residues of the SARS-CoV-2 spike protein (S-protein), blocking trimer formation and interaction with the human receptor hACE2, as well as with the main 3C-like protease (3CLpro), inhibiting their biological function. Our data may represent a step forward in the search for potential new chemotherapeutic agents for the treatment of COVID-19.
... FAAH2, is a fatty acid hydrolase involved in endocannabinoid uptake and inactivation [99]. Cannabinoids may reduce pulmonary inflammation through immunomodulation, decrease polymorphonuclear leukocytes infiltration, reduce fibrosis, decrease viral replication, and modulate the 'cytokine storm' in COVID-19 [100][101][102][103]. Cannabinoids have been suggested as anti-inflammatory treatment in COVID-19 [102,103]. ...
... FAAH2, is a fatty acid hydrolase involved in endocannabinoid uptake and inactivation [99]. Cannabinoids may reduce pulmonary inflammation through immunomodulation, decrease polymorphonuclear leukocytes infiltration, reduce fibrosis, decrease viral replication, and modulate the 'cytokine storm' in COVID-19 [100][101][102][103]. Cannabinoids have been suggested as anti-inflammatory treatment in COVID-19 [102,103]. Our results are also consistent with LCTL, being protective against hospitalization. LCTL is a glycosidase which hydrolyses glycosidic bonds. ...
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In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12–1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80–0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86–0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.
... In particular, it has been demonstrated that the mitochondria impairment caused by the alteration of iron homeostasis is implicated into pathogenesis of systemic lupus erythematosus (SLE), leading to a chronic inflammatory state [23]. Moreover, in coronavirus disease 2019 (COVID-19), a severe systemic inflammatory disease [27], a lot of complications are closely related to intracellular iron accumulation which is consequently responsible for mitochondria function alteration, determining free radicals, ROS, and pro-inflammatory factors release [28]. Another subcellular organelle damaged by iron metabolism impairment is represented by the lysosome. ...
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Iron is a crucial element for mammalian cells, considering its intervention in several physiologic processes. Its homeostasis is finely regulated, and its alteration could be responsible for the onset of several disorders. Iron is closely related to inflammation; indeed, during inflammation high levels of interleukin-6 cause an increased production of hepcidin which induces a degradation of ferroportin. Ferroportin degradation leads to decreased iron efflux that culminates in elevated intracellular iron concentration and consequently iron toxicity in cells and tissues. Therefore, iron chelation could be considered a novel and useful therapeutic strategy in order to counteract the inflammation in several autoimmune and inflammatory diseases. Several iron chelators are already known to have anti-inflammatory effects, among them deferiprone, deferoxamine, deferasirox, and Dp44mT are noteworthy. Recently, eltrombopag has been reported to have an important role in reducing inflammation, acting both directly by chelating iron, and indirectly by modulating iron efflux. This review offers an overview of the possible novel biological effects of the iron chelators in inflammation, suggesting them as novel anti-inflammatory molecules.
... Cannabinoids are well-known for their anti-angiogenic and anti-inflammatory potentials (Norooznezhad and Norooznezhad 2017;Baban et al. 2021). So far, some studies have suggested these compounds as a possible treatment for COVID-19 among which none have discussed their potential to inhibit endothelial cell dysfunction or pathologic angiogenesis (Rossi et al. 2020;Costiniuk and Jenabian 2020;Mohammed et al. 2020;Malinowska et al. 2021). Regarding the role of angiogenesis and endothelial dysfunction in the pathogenesis of COVID-19 and the already mentioned potent anti-inflammatory properties of CBD, it seems that this compound might be effective in the treatment of severe COVID-19 by affecting multiple pathways. ...
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Background Among pathways involved in the pathogenesis of coronavirus disease 2019 (COVID-19), impaired endothelial cell (EC) function and angiogenesis have been discussed less frequently than others such as cytokine storm. These two do play parts in the development of various clinical manifestations of COVID-19 including acute respiratory distress syndrome (ARDS) and the hyper-coagulation state. Methods This narrative review attempts to gather recent data on the possible potential of cannabidiol in the treatment of COVID-19 with an eye on angiogenesis and endothelial dysfunction. Keywords including cannabidiol AND angiogenesis OR endothelial cell as well as coronavirus disease 2019 OR COVID-19 AND angiogenesis OR endothelial dysfunction were searched among the databases of PubMed and Scopus. Results Cannabidiol (CBD), as a therapeutic phytocannabinoid, has been approved by the Food and Drug Administration (FDA) for two types of seizures. Due to the potent anti-inflammatory properties of CBD, this compound has been suggested as a candidate treatment for COVID-19 in the literature. Although its potential effect on ECs dysfunction and pathologic angiogenesis in COVID-19 has been overlooked, other than cytokines like interleukin 1β (IL-β), IL-6, IL-8, and tumour necrosis factor α (TNFα) that are common in inflammation and angiogenesis, CBD could affect other important factors related to ECs function and angiogenesis. Data shows that CBD could decrease pathologic angiogenesis via decreasing ECs proliferation, migration, and tube formation. These activities are achieved through the suppression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), urokinase plasminogen activator (uPA), matrix metalloproteinase 2 (MMP-2), MMP-9, intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, in an animal model, ARDS and sepsis responded well to CBD treatment. Conclusion Altogether and considering the current use of CBD in the clinic, the conduction of further studies on CBD administration for patients with COVID-19 seems to be useful.
... CBD, due to its high effectiveness in reducing inflammation by activating CB2 receptors, may prove useful in reducing inflammation and lung damage in patients infected with SARS-CoV-2 [5,32]. ...
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The COVID-19 pandemic caused by the SARS-CoV-2 virus made it necessary to search for new options for both causal treatment and mitigation of its symptoms. Scientists and researchers around the world are constantly looking for the best therapeutic options. These difficult circumstances have also spurred the re-examination of the potential of natural substances contained in Cannabis sativa L. Cannabinoids, apart from CB1 and CB2 receptors, may act multifacetedly through a number of other receptors, such as the GPR55, TRPV1, PPARs, 5-HT1A, adenosine and glycine receptors. The complex anti-inflammatory and antiviral effects of cannabinoids have been confirmed by interactions with various signaling pathways. Considering the fact that the SARS-CoV-2 virus causes excessive immune response and triggers an inflammatory cascade, and that cannabinoids have the ability to regulate these processes, it can be assumed that they have potential to be used in the treatment of COVID-19. During the pandemic, there were many publications on the subject of COVID-19, which indicate the potential impact of cannabinoids not only on the course of the disease, but also their role in prevention. It is worth noting that the anti-inflammatory and antiviral potential are shown not only by well-known cannabinoids, such as cannabidiol (CBD), but also secondary cannabinoids, such as cannabigerolic acid (CBGA) and terpenes, emphasizing the role of all of the plant’s compounds and the entourage effect. This article presents a narrative review of the current knowledge in this area available in the PubMed, Scopus and Web of Science medical databases.
... Suppression of the inflammatory reaction in some viral infections can lead to increased replication of the virus, exacerbation of the disease, and even death. Furthermore, damage to the respiratory epithelium increases the risk of concomitant bacterial infections and sepsis in patients with COVID-19 [166,167]. ...
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Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... 156 Currently, different studies suggest the therapeutic potential of cannabinoids in COVID-19 pandemic. [157][158][159] In contrast, Frei et al showed that CB2 activation enhanced migratory responsiveness of eosinophils in an OVA-asthma mouse models. 160 Accordingly, the lack of CB2 decreased allergic inflammation in asthma and dermatitis mouse model. ...
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Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti‐inflammatory, antipyretic and analgesic effects are applied against symptoms of respiratory infections, including SARS‐CoV‐2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID‐19 also revealed the gaps in our understanding of their mechanism of action, selectivity and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs‐exacerbated respiratory disease (NERD). In this context, the consensus report summarises currently available knowledge, novel discoveries and controversies regarding the use of NSAIDs in COVID‐19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID‐19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarise the major knowledge gaps and unmet needs in current eicosanoid research.
Aim: Coronavirus disease still poses a global health threat which advocates continuous research efforts to develop effective therapeutics. Materials & methods: We screened out an array of 29 cannabis phytoligands for their viral spike-ACE2 complex and main protease (Mpro) inhibitory actions by in silico modeling to explore their possible dual viral entry and replication machinery inhibition. Physicochemical and pharmacokinetic parameters (ADMET) formulating drug-likeness were computed. Results: Among the studied phytoligands, cannabigerolic acid (2), cannabigerol (8), and its acid methyl ether (3) possessed the highest binding affinities to SARS-CoV-hACE2 complex essential for viral entry. Canniprene (24), cannabigerolic methyl ether (3) and cannabichromene (9) were the most promising Mpro inhibitors. Conclusion: These non-psychoactive cannabinoids could represent plausible therapeutics with added-prophylactic value as they halt both viral entry and replication machinery.
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In late 2019, COVID-19 emerged in Wuhan, China. Currently, it is an ongoing global health threat stressing the need for therapeutic compounds. Linking the virus life cycle and its interaction with cell receptors and internal cellular machinery is key to developing therapies based on the control of infectivity and inflammation. In this framework, we evaluate the combination of cannabidiol (CBD), as an anti-inflammatory molecule, and terpenes, by their anti-microbiological properties, in reducing SARS-CoV-2 infectivity. Our group settled six formulations combining CBD and terpenes purified from Cannabis sativa L, Origanum vulgare, and Thymus mastichina. The formulations were analyzed by HPLC and GC-MS and evaluated for virucide and antiviral potential by in vitro studies in alveolar basal epithelial, colon, kidney, and keratinocyte human cell lines. Conclusions and impact: We demonstrate the virucide effectiveness of CBD and terpene-based formulations. F2TC reduces the infectivity by 17%, 24%, and 99% for CaCo-2, HaCat, and A549, respectively, and F1TC by 43%, 37%, and 29% for Hek293T, HaCaT, and Caco-2, respectively. To the best of our knowledge, this is the first approach that tackles the combination of CBD with a specific group of terpenes against SARS-CoV-2 in different cell lines. The differential effectiveness of formulations according to the cell line can be relevant to understanding the pattern of virus infectivity and the host inflammation response, and lead to new therapeutic strategies.
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“COVID-19” is the word that certainly isn’t forgotten by everybody who lives in the first half of the twenty-first century. COVID-19, as a pandemic, has led many researchers from different biomedical fields to find solutions or treatments to manage the pandemic. However, no standard treatment for this disease has been discovered to date. Probably, preventing the severe acute respiratory infection form of COVID-19 as the most dangerous phase of this disease can be helpful for the treatment and reduction of the death rate. In this regard, mesenchymal stem cells (MSCs)-based immunomodulation treatment has been proposed as a suitable therapeutic approach and several clinical trials have begun. Recently, MSCs according to their immunomodulatory and regenerative properties attract attention in clinical trials. After the intravenous transplantation of MSCs, a significant population of cells accumulates in the lung, which they alongside immunomodulatory effect could protect alveolar epithelial cells, reclaim the pulmonary microenvironment, prevent pulmonary fibrosis, and cure lung dysfunction. Given the uncertainties in this area, we reviewed reported clinical trials and hypotheses to provide useful information to researchers and those interested in stem cell therapy. In this study, we considered this new approach to improve patient’s immunological responses to COVID-19 using MSCs and discussed the aspects of this proposed treatment. However, currently, there are no approved MSC-based approaches for the prevention and/or treatment of COVID-19 patients but clinical trials ongoing.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that has resulted in nearly 1,000,000 laboratory-confirmed cases including over 50,000 deaths. Although SARS-CoV-2 and SARS-CoV share a number of common clinical manifestations, SARS-CoV-2 appears to be highly efficient in person-to-person transmission and frequently cause asymptomatic infections. However, the underlying mechanism that confers these viral characteristics on high transmissibility and asymptomatic infection remain incompletely understood. Methods: We comprehensively investigated the replication, cell tropism, and immune activation profile of SARS-CoV-2 infection in human lung tissues with SARS-CoV included as a comparison. Results: SARS-CoV-2 infected and replicated in human lung tissues more efficiently than that of SARS-CoV. Within the 48-hour interval, SARS-CoV-2 generated 3.20 folds more infectious virus particles than that of SARS-CoV from the infected lung tissues (P<0.024). SARS-CoV-2 and SARS-CoV were similar in cell tropism, with both targeting types I and II pneumocytes, and alveolar macrophages. Importantly, despite the more efficient virus replication, SARS-CoV-2 did not significantly induce types I, II, or III interferons in the infected human lung tissues. In addition, while SARS-CoV infection upregulated the expression of 11 out of 13 (84.62%) representative pro-inflammatory cytokines/chemokines, SARS-CoV-2 infection only upregulated 5 of these 13 (38.46%) key inflammatory mediators despite replicating more efficiently. Conclusions: Our study provided the first quantitative data on the comparative replication capacity and immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Our results provided important insights on the pathogenesis, high transmissibility, and asymptomatic infection of SARS-CoV-2.
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CoV-19/SARS-CoV-2 is a highly pathogenic virus that causes coronavirus-19 disease (COVID-19) an acute respiratory distress syndrome which provokes serious problems for global health. Studies suggest that there are many differences between men and women in the immune response to CoV-19 infection and inflammatory diseases. Women, compared to men, are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes. The presence of two X chromosomes in women emphasize the immune system even if one is inactive. The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less inflammation than in man, while CD4+ T cells are higher with better immune response. In addition, women generally produce higher levels of antibodies which remain in the circulation longer. The levels of activation of the immune cells are higher in women than in men, and it is correlated with the trigger of TLR7 and the production of IFN. TLR7 is higher in women than in men and its biallelic expression leads to higher immune responses and increases the resistance to viral infections. TLR7 is expressed in innate immune cells which recognizes single strand RNA virus by promoting the production of antibodies against the virus and the generation of pro-inflammatory cytokines including IL-6 and IL-1 family members. Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity. In addition, on the X chromosome there are loci that code for the genes involved in the regulation of immune cells such as FOXP3, and transcription factor for Treg involved in virus pathogenesis. The X chromosome influences the immune system by acting on many other proteins, including TLR8, CD40L and CXCR3 which can be over-expressed in women, and influence the response to viral infections and vaccinations. However, the biallelic expression of the X-linked genes can promote harmful autoimmune and inflammatory responses. Cardiovascular diseases are more frequent in males and subjects without cardiovascular dysfunctions infected by CoV-19 have a better prognosis. ACE2 is a receptor for CoV-19 and protects lung damage. CoV-19 infection and the virus's Spike protein inhibit the expression of ACE2, abolishing its protective function. Inhibitors of the angiotensin converting enzyme (ACEI) are used to stem the devastating effects of CoV-19, to increase the number of CD3 and CD8 T cells and to reduce the viral load and IL-6 levels that control CoV-19 replication via NF-B, but these effects are still under study. It is hoped that certain drugs, such as CoV-19 receptor blockers, anti-inflammatories (against rheumatic diseases), monoclonal antibodies, anti-IL-1 and anti-IL-6, the remdesevir drug (analogue adenosine, effective against ebola), hydroxychloroquine (for the treatment of malaria) and vaccines, will open up new strategies and new therapeutic ways to combat this terrible virus.
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Background and aims The outbreak of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has recently spread worldwide and been declared a pandemic. We aim to describe here the various clinical presentations of this disease by examining eleven cases. Methods Electronic medical records of 11 patients with COVID‐19 were collected and demographics, clinical manifestations, outcomes, key laboratory results, and radiological images are discussed. Results The clinical course of the eleven cases demonstrated the complexity of the COVID‐19 profile with different clinical presentations. Clinical manifestations range from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Laboratory detection of the viral nucleic acid can yield false‐negative results, and serological testing of virus specific IgG and IgM antibodies should be used as an alternative for diagnosis. Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with a pre‐existing condition of chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were more severe. Conclusion All different clinical characteristics of COVID‐19 should be taken into consideration to identify patients that need to be in strict quarantine for the efficient containment of the pandemic.
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The new coronavirus (SARS-CoV-2) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted “CellPhoneDB” analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
The outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China has been brought to global attention and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Scientific advancements since the pandemic of severe acute respiratory syndrome (SARS) in 2002~2003 and Middle East respiratory syndrome (MERS) in 2012 have accelerated our understanding of the epidemiology and pathogenesis of SARS-CoV-2 and the development of therapeutics to treat viral infection. As no specific therapeutics and vaccines are available for disease control, the epidemic of COVID-19 is posing a great threat for global public health. To provide a comprehensive summary to public health authorities and potential readers worldwide, we detail the present understanding of COVID-19 and introduce the current state of development of measures in this review.
Background The 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries with cases reported worldwide. This novel Coronavirus Disease (COVID-19) is associated with a respiratory illness that may cause severe pneumonia and acute respiratory distress syndrome (ARDS). Although related to the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiological and clinical features which have not been completely understood to date. Objectives We provide a review of the differences in terms of pathogenesis, epidemiology and clinical features between COVID-19, SARS and MERS. Sources The most recent literature in English language regarding COVID-19 has been reviewed and extracted data have been compared with the current scientific evidence about SARS and MERS epidemics. Content COVID-19 seems not to be very different from SARS regarding its clinical features. However, it has a fatality rate of 2.3%, lower than SARS (9.5%) and much lower than MERS (34.4%). It cannot be excluded that because of the COVID-19 less severe clinical picture it can spread in the community more easily than MERS and SARS. The actual basic reproductive number (R0) of COVID-19 (2-2.5) is still controversial. It is probably slightly higher than the R0 of SARS (1.7-1.9) and higher than MERS (<1),. The gastrointestinal route of transmission of SARS-CoV-2, which has been also assumed for SARS-CoV and MERS-CoV, cannot be ruled out and needs to be further investigated. Implications There is still much more to know about COVID-19, especially as concerns mortality and capacity of spreading on a pandemic level. Nonetheless, all of the lessons we learned in the past from SARS and MERS epidemics are the best cultural weapons to face this new global threat.
Importance Virus infection has been widely described as one of the most common causes of myocarditis. However, less is known about the cardiac involvement as a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective To describe the presentation of acute myocardial inflammation in a patient with coronavirus disease 2019 (COVID-19) who recovered from the influenzalike syndrome and developed fatigue and signs and symptoms of heart failure a week after upper respiratory tract symptoms. Design, Setting, and Participant This case report describes an otherwise healthy 53-year-old woman who tested positive for COVID-19 and was admitted to the cardiac care unit in March 2020 for acute myopericarditis with systolic dysfunction, confirmed on cardiac magnetic resonance imaging, the week after onset of fever and dry cough due to COVID-19. The patient did not show any respiratory involvement during the clinical course. Exposure Cardiac involvement with COVID-19. Main Outcomes and Measures Detection of cardiac involvement with an increase in levels of N-terminal pro–brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T, echocardiography changes, and diffuse biventricular myocardial edema and late gadolinium enhancement on cardiac magnetic resonance imaging. Results An otherwise healthy 53-year-old white woman presented to the emergency department with severe fatigue. She described fever and dry cough the week before. She was afebrile but hypotensive; electrocardiography showed diffuse ST elevation, and elevated high-sensitivity troponin T and NT-proBNP levels were detected. Findings on chest radiography were normal. There was no evidence of obstructive coronary disease on coronary angiography. Based on the COVID-19 outbreak, a nasopharyngeal swab was performed, with a positive result for SARS-CoV-2 on real-time reverse transcriptase–polymerase chain reaction assay. Cardiac magnetic resonance imaging showed increased wall thickness with diffuse biventricular hypokinesis, especially in the apical segments, and severe left ventricular dysfunction (left ventricular ejection fraction of 35%). Short tau inversion recovery and T2-mapping sequences showed marked biventricular myocardial interstitial edema, and there was also diffuse late gadolinium enhancement involving the entire biventricular wall. There was a circumferential pericardial effusion that was most notable around the right cardiac chambers. These findings were all consistent with acute myopericarditis. She was treated with dobutamine, antiviral drugs (lopinavir/ritonavir), steroids, chloroquine, and medical treatment for heart failure, with progressive clinical and instrumental stabilization. Conclusions and Relevance This case highlights cardiac involvement as a complication associated with COVID-19, even without symptoms and signs of interstitial pneumonia.
The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical ill COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.