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Oncotarget1
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www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2016
Impacts of cigarette smoking on immune responsiveness: Up
and down or upside down?
Feifei Qiu1, Chun-Ling Liang1, Huazhen Liu1, Yu-Qun Zeng2, Shaozhen Hou3, Song
Huang3, Xiaoping Lai3, Zhenhua Dai1
1Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences and Guangdong Provincial Hospital of
Chinese Medicine, Guangzhou, Guangdong, China
2Department of Nephrology, The Second Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,
Guangdong, China
3School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
Correspondence to: Zhenhua Dai, email: zdai2009@outlook.com
Keywords: cigarette smoking, immunoregulation, adaptive immunity, and innate immunity
Received: September 16, 2016 Accepted: November 12, 2016 Published: November 25, 2016
ABSTRACT
Cigarette smoking is associated with numerous diseases and poses a serious
challenge to the current healthcare system worldwide. Smoking impacts both
innate and adaptive immunity and plays dual roles in regulating immunity by
either exacerbation of pathogenic immune responses or attenuation of defensive
immunity. Adaptive immune cells affected by smoking mainly include T helper cells
(Th1/Th2/Th17), CD4+CD25+ regulatory T cells, CD8+ T cells, B cells and memory
T/B lymphocytes while innate immune cells impacted by smoking are mostly DCs,
macrophages and NK cells. Complex roles of cigarette smoke have resulted in numerous
diseases, including cardiovascular, respiratory and autoimmune diseases, allergies,
cancers and transplant rejection etc. Although previous reviews have described the
effects of smoking on various diseases and regional immunity associated with specic
diseases, a comprehensive and updated review is rarely seen to demonstrate impacts
of smoking on general immunity and, especially on major components of immune cells.
Here, we aim to systematically and objectively review the inuence of smoking on
major components of both innate and adaptive immune cells, and summarize cellular
and molecular mechanisms underlying effects of cigarette smoking on the immune
system. The molecular pathways impacted by cigarette smoking involve NFκB, MAP
kinases and histone modication. Further investigations are warranted to understand
the exact mechanisms responsible for smoking-mediated immunopathology and to
answer lingering questions over why cigarette smoking is always harmful rather than
benecial even though it exerts dual effects on immune responses.
INTRODUCTION
Cigarette smoking is prevalent worldwide and it has
been reported that approximately 1/3 of the adult population
smokes tobacco [1]. Smoke from tobacco combustion
contains numerous harmful chemicals, including, but not
limited to, carbon monoxide, nicotine, nitrogen oxides
and cadmium [2, 3]. Exposure of tobacco smoke has been
considered as an important cause of preventable death
worldwide [4, 5] and related to the development of brain,
respiratory, cardiovascular diseases, infections and cancers
[6–9] (Table 1). Meanwhile, smoking has been implicated
in the production of many immune or inammatory
mediators, including both pro-inammatory and anti-
inammatory cytokines [10–14]. Recently, many studies
have demonstrated that cigarette smoking has far-reaching
effects on chronic inammation and autoimmunity at a
systemic level [2, 10, 15, 16], including rheumatoid arthritis
(RA), psoriasis, chronic obstructive pulmonary disease
(COPD) and systemic lupus erythematosus (SLE). Although
reviews have been previously conducted to describe effects
of cigarette smoking on various diseases and local immunity
associated with a specic disease, a comprehensive review
demonstrating impacts of cigarette smoking on major
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Table 1: Major diseases caused by cigarette smoking
Disease Disease Disease
Cancers Lung cancer Autoimmune
diseases
Rheumatoid arthritis Graft rejection Cardiovascular
graft
Renal carcinoma Chronic obstructive
pulmonary disease Renal graft
Bladder cancer Systemic lupus
erythematosus
Lung
transplantaion
Pancreatic carcinoma Inammatory bowel
disease
Cardiac
transplantation
Breast cancer Crohn's disease Hepatic
transplantation
Hepatocellular cancer Ulcerative colitis Lower extremity
bypass
Esophageal squamous
cell carcinoma Psoriatic arthritis Infrainguinal
bypass
Oral cavity cancer Ankylosing
spondylitis Skin graft
Pharynx cancer Systemic sclerosis
Hematopoietic
stem cell
transplantation
Nasopharynx carcinoma Diabetes mellitus
Oral and
respiratory
diseases
Acute eosinophilic
pneumonia
Stomach cancer Macular degeneration Asthma
Uterine cervix cancer Graves'
hyperthyroidism
Chronic
obstructive
pulmonary disease
Myeloid leukaemia Goodpasture's
syndrome
Hypersensitivity
pneumonitis
Pregnancy Preterm birth Thromboangiitis
obliterans
Rhinitis
Fetal growth restriction Primary biliary
cirrhosis Periodontitis
Placental abrubtion Neurological
diseases Alzheimer's Disease Gingivitis
Placenta previa Stroke Recurrent
wheezing
Low birthweight Small vessel ischemic
disease
Cardiovascular
diseases
Myocardial
infarction
Sudden infant death
syndrome Cerebral aneurysms Cardiac
arrhythmia
Silent cerebral
infarction Atherothrombosis
Parkinson's disease Thromboangiitis
obliterans
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components of immune cells is lacking. We have previously
found that smoking hinders long-term allograft survival
induced by costimulatory blockade [17]. Here, we aim to
systematically review dual inuences of smoking on main
components of immune cells of both innate and adaptive
immunity, and summarize the molecular and cellular
mechanisms underlying the effects of cigarette smoking on
the immune cells.
EFFECTS OF CIGARETTE SMOKING
ON ADAPTIVE IMMUNITY
T lymphocytes
T lymphocytes (T cells) are a major subset of
immune cells mediating adaptive immunity. In general,
activation and differentiation of naive T cells upon antigen
recognition generate effector T cells and, at a small
frequency, memory and regulatory T cells [18–24]. These
cells exert their functions in response to specic antigens
through their helper, effector, cytotoxic or regulatory
capacities. Previous studies have shown the profound
impacts of cigarette smoking on T cells and their release
of proinammatory mediators (Figure 1).
T helper cells
Epidemiological studies have suggested that either
rsthand or secondhand tobacco smoking is an important
contributor in the development of many diseases. It’s
been known that cigarette smoking is a major cause of
COPD characterized by chronic airow obstruction [25].
Forsslund et al [26] analyzed T cells in bronchoalveolar
lavage (BAL) uid and peripheral blood from 40 non-
smokers, 40 smokers with normal pulmonary function
and 38 COPD patients. They found that the percentage
of CD8+ BAL cells of smoking groups was higher than
that of non-smoking groups while the frequency of CD4
+
T cells in both BAL and blood of smokers was lower
than that of non-smokers. Zhang et el. [27] found that the
homeostasis of circulating T helper cells was disrupted
in chronic COPD patients compared with healthy non-
smokers. Second-hand smoke (SHS) also affected T
cell components. Analyses of blood cotinine, a nicotine
metabolite, and T-cell subpopulations from non-smokers
demonstrated that passive smoking was positively
correlated with the prevalence of naive CD3+ T cells [28].
Taken together, active smoking increases the percentage
of CD8+ T cells but lowers CD4+ T cells in humans while
passive smoking generally augments human CD3+ T cells.
Further studies demonstrated that the percentage
of Th17 cells in circulating T cell subsets from COPD
patients was higher than that of current smokers without
COPD and healthy subjects while the percentage of Th1
cells was also increased in COPD patients and current
smokers without COPD [29]. Mice with COPD induced
by chronic tobacco smoke also exhibited a rise in Th17
subset accompanying with upregulation of Th17-series
of cytokines (IL-6, IL-17A and IL-23) in the lung tissue
Figure 1: Effects of cigarette smoking on the development and function of both innate and adaptive immune cells.
Cigarette smoking alters the development, cytokine production, and effector function of both innate immune cells, including DCs,
macrophages and NK cells, and adaptive immune cells, such as cytotoxic CD8+ T cells, CD4+ Th cells, regulatory T cells and B cells,
leading to pro-inammatory responses and/or dysfunction of immune cells. (“Altered” denotes contradictory results with both upregulation
and downregulation)
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and peripheral blood [30]. A study on BAL from mice,
which were exposed to tobacco smoke for at least six
months, showed that the number of Th1 and Th17 cells
was signicantly elevated [31]. Mice with emphysema
had an increased expression of Th1-type cytokine IFN-γ
and Th17-type IL-17A [32, 33] and/or augmented
numbers of Th17/Tc17 and Tc1 cells [33, 34]. Therefore,
both murine experiments and human studies suggest that
increases in Th1 and Th17 cell subsets are associated
with pulmonary inammation as a result of cigarette
smoke exposure (CSE).
Crohn’s disease (CD) is a chronic inammatory
bowel disease that leads to obvious morbidity [35], and is
epidemiologically correlated with cigarette smoking [36,
37]. Many studies have revealed that immune responses
mediated by Th1 and Th17 cells play an important role
in CD [38–40], and that nicotine, a major component of
tobacco smoke, can worsen the trinitrobenzene sulfonic
acid (TNBS)-induced colitis in mice with an increased
percentage of Th17 cells [41]. In contrast, CSE was found
to have a different effect on Th17 cells in ulcerative colitis.
Nicotine relieved oxazolone-induced colitis and reduced
the number of Th17 cells in mice [41]. Montbarbon et
al pretreated C57BL/6 mice with cigarette smoke for 14
days and then induced their colitis by dextran sodium
sulfate (DSS). They observed that smoke exposure
improved colonic inammation with an obviously reduced
production of colonic Th1/Th17 cytokines, including
TNFα, IFN-γ and IL-17 [42]. The contradictory effects
of smoke/nicotine on two types of experimental colitis
in mice resulted from different pathologic changes. It
has been known that TNBS-induced colitis was Th1 cell-
mediated whereas oxazolone-induced colitis was Th2
cell-oriented [43, 44]. Galitovskiy et al. [41] showed that
Th1 cytokine IL-12 signicantly decreased the protein
expression of α7 nicotinic acetylcholine receptors (α7
nAChR), which was expressed on murine CD4+ T cells
and relayed anti-inammatory signals, while Th2 cytokine
IL-4 enhanced α7 nAChR expression. Therefore, nicotine
exhibited dual effects on colitis of differential animal
models due to the opposite expression prole of anti-
inammatory α7 nAChR. CSE also inuenced other
autoimmune diseases by regulating Th17 responses.
Torii et al. evaluated the percentage of circulating Th17
among CD3+ cells in peripheral blood mononuclear cells
(PBMCs) of psoriatic patients and found that smokers
had higher levels of Th17+ T cells than non-smokers and
that tobacco smoke extract enhanced Th17 generation in
vitro [45]. Moreover, smoking was suggested to induce
rheumatoid arthritis by promoting Th17 responses through
Aryl hydrocarbon receptor on human T cells [46, 47].
Th2 cells are mainly primed by IL-4 and secrete
effector cytokines against extracellular parasites. It
was reported that CSE exacerbated the Th2-mediated
airway inammation in mice treated with OVA [48], and
enhanced mRNA and protein expression of thymic stromal
lymphopoietin [49], which was important for Th2-specic
allergic inammation. It was also observed that prenatal
secondhand smoke signicantly elevated the secretion of
Th2 cytokines, including IL-4 and IL-13, and promoted
activation and polarization of Th2 cells and pulmonary
inammation in BALB/C mice [50, 51]. Mishra et al. [52]
revealed that nicotine treatments to Brown Norway rats,
which were sensitized with allergens, apparently reduced
the expression level of pulmonary Th2-related chemokines
and cytokines, and inhibited eosinophil migration. These
animal studies indicate that cigarette smoking mostly
promotes Th2 immune responses as well as Th2-related
pulmonary inammation and asthma, although nicotine
may attenuate allergy via reducing Th2 responses.
In summary, data from both human and animal
studies indicate that Th17 cell is actively involved
in worsening smoking-associated inammation and
autoimmune diseases, including COPD, CD, colitis,
RA and psoriasis, although nicotine can mitigate colitis
in mice via suppression of IL-17 expression. Moreover,
cigarette smoking may promote autoimmune diseases by
enhancing Th1 polarization. Smoking also promotes Th2-
mediated pulmonary inammation and allergy in animal
studies. Further investigations, especially in humans, are
needed to provide mechanistic insight into the effects of
cigarette smoke on Th1/Th2/Th17 responses and allergy
or autoimmune diseases mediated by these T helper cells.
CD8+ T cells
CD8+ T cells are also known as cytotoxic T
lymphocytes (CTLs), which play an important role in
host immune defense via killing infected or damaged
cells. It was reported that chronic CSE could not induce
inammation or immune responses and emphysema in
CD8 knockout mice [53]. Further studies demonstrated
that IP-10 from CD8
+
T cells facilitated the production of
macrophage elastase, contributing to elastin fragmentation
and pulmonary injury [53]. These results indicated that
CD8
+
T cells serve as a key mediator of COPD. Nadigel et
al. [54] found that human CD8+ T cells, either from lung
tissue of COPD patients or exposed to cigarette smoke
condensate, expressed more TLR4 and TLR9 proteins
as compared with controls, while CSE also induced the
activation of circulating CD8+ T cell with an increase
in cytokine expression. Moreover, analysis of clinical
specimens from 9 smokers with COPD and 7 healthy
smokers for lung resection showed that CD8+ T cells
were also increased in the peripheral airways of COPD
patients compared with healthy smokers [55], and their
proliferation was induced by CSE [56, 57]. Another
study on emphysema mice demonstrated that cigarette
smoke not only increased the percentage of IL-21
+
Th17
and IL-21R+ CD8+ T cells in peripheral blood, but also
enhanced their expressions of IL-17 and IL-21, which
in turn upregulated perforin and granzyme B in CD8+ T
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cells, indicating that cytotoxic function of CD8 + T cells
can be regulated by Th17 cells in emphysema [58]. On
the contrary, early investigation had revealed that smokers
with COPD (n=12) had less circulating CD8
+
T cells and
more chemokine receptor CXCR3 on CD8+ T cells than
smokers without COPD (n=14) and nonsmokers (n=13),
while smokers with and without COPD had more activated
and cytotoxic (CD27-CD45RA+) CD8+ T cells in the
peripheral blood than normal nonsmokers [59].
In conclusion, overwhelming majority of studies in
humans have shown that smoking increases the number
of CD8+ T cells and their activation and function. The
contradictory data from initial studies showing a reduction
in human CD8+ T cell numbers under the smoking
condition could be attributed to gender and genetic
background or racial difference. However, studies in both
humans and animals indicate that cigarette smoke not just
alters the total number of CD8+ T cells, but also induces
or enhances their functional responses. Meanwhile, these
ndings suggest that the inuences of cigarette smoking
on CD8+ T cells may vary, depending on the differential
tissue microenvironment and pathological conditions.
Regulatory T cell (Treg)
Tregs play an essential role in maintaining
immunologic homeostasis and tolerance through
its immunosuppressive capacity. Epidemiologic
investigations have revealed that smoke exposure is
associated with the imbalance of Tregs in COPD patients
or smokers. Barceló et al. [60] reported a signicant
downregulation of CD4+ CD25+ Treg cells in BAL uid
of patients with COPD compared with healthy smokers.
Subsequent analyses by other groups demonstrated a
similar tendency in circulating CD4
+
and CD8
+
Tregs of
COPD patients [61, 62]. Furthermore, smoking or passive
cigarette smoke exposure during gestation contributed to
reduced Treg numbers in cord blood [63], resulting in a
higher risk of neonatal atopic dermatitis and food allergy.
On the other hand, mounting evidence demonstrated that
COPD patients had a prominent increase in Treg cells.
The analysis of BLA uid from smokers and COPD
patients showed that the percentage of CD4
+
CD25
+
Tregs
was augmented compared with healthy non-smokers
[64–66]. Moreover, the prevalence of CD4+FoxP3+
Treg cells was also elevated in the pulmonary tissue
and peripheral blood of COPD patients compared with
non-smokers [29, 67]. Although an increased frequency
of CD4+CD25+ T cells was observed in smokers with
normal pulmonary function, the alteration of FoxP3+
and CD127+ expression was not seen when compared
to non-smokers [66]. Three subpopulations of human
Tregs were reported. The suppressive subpopulations
contained both resting CD25++CD45RA+ Tregs (rTregs)
and activated CD25
+++
CD45RA
-
Tregs (aTregs) while the
pro-inammatory subpopulations were cytokine-secreting
CD25++CD45RA- (FrIII) cells [68]. Hou et al [69] found
that COPD patients had a lower percentage of suppressive
Tregs (rTregs and aTregs) but higher percentage of
FrIII cells compared with healthy smokers, although the
frequencies of three subsets of Tregs were all increased
in smokers compared to non-smokers, suggesting that
Treg imbalance (aTreg+rTreg vs. Fr III) has an impact on
pathogenesis of COPD.
Taken together, impacts of cigarette smoking on
human Treg numbers remain contradictory. We propose
that cigarette smoking impairs immunosuppressive
function of Tregs by reducing the number of suppressive
Tregs or increasing the prevalence of non-suppressive
Tregs, leading to an enhanced autoimmune component in
COPD pathogenesis, while increased Treg numbers may
occur in some smokers under circumstances, leading to
worsened respiratory infections. More in-depth studies
are required to clearly dene net impacts of cigarette
smoking on Treg generation and function in smokers with
or without a specic medical condition.
B cells
Recent investigations have focused on the
mechanisms underlying smoking-induced changes in
distribution and function of B cells. Epidemiologic
studies showed that cigarette smoking resulted in higher
prevalence of (class-switched) memory B cells in
peripheral blood and memory IgG+ B cells in the lung
[70, 71]. Smokers also exhibited an elevated level of
circulating IgE, leading to the potential development of
atopic diseases and asthma [72]. It has been reported that
nicotinic receptors, including alpha4 and alpha7 subunits,
are present and play important roles in B cell lines [73,
74]. Chronic nicotine exposure increased the expression
of alpha4 and alpha7 subunits and induced proliferation of
hybridoma B cells [73]. A retrospective study on prostate
inammation showed that the risk of acute inammation
of current smokers was higher than that of former smokers
(OR, 1.35; P, 0.001) and never-smokers (OR, 1.36; P,
0.001), and the risk of chronic inammation in the baseline
biopsy was related with current smoking, indicating that
cigarette smoking was correlated with acute and chronic
prostatic inammation [75]. Cigarette smoking also caused
inammation in prostate cancer and a B cell signature in
prostate tumors in current smokers, contributing to an
increase in the expression of immunoglobulin by B cells
inltrating the tumor [76]. On the other hand, smokers
with Helicobacter pylori (H. pylori) infection had a lower
number and impaired function of regulatory B cells than
non-smokers with also H. pylori infection [77]. Moreover,
analyses of immunoglobulins demonstrated a decreased
production of IgA, IgG and IgM in smokers [78–80]
while a study on the avidity of IgG using modied VLP
ELISAs revealed that the higher risk of having the low
avidity of HPV16/18 IgG in B cells was also associated
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with cigarette smoking [81]. Recent investigations have
focused on the mechanisms underlying smoking-induced
distribution and development of B cells. They developed
from bone marrow-derived hematopoietic stem cells that
rst differentiated into precursor and progenitor B cells
and then immature B cells [82]. It was found that tobacco
smoke exposure led to obvious downregulation of murine
marrow B220+CD34- pre-B cells and/or B220+CD34+
pro-B cells without signicant changes in cell apoptosis
and cell cycle [83, 84].
In summary, studies on humans again have
generated contradictory data showing that cigarette
smoking increases frequency of memory B cells and
IgE production, lowers regulatory B cell numbers, but
decreases production of IgA, IgG and IgM in smokers
while smoke exposure downregulates murine marrow
pre-B cells or pro-B cells. Meanwhile, smoking raises
the risk of inammation in prostate cancer and B cell
signature in the tumors.
Memory lymphocytes
Memory T cells are a subset of T lymphocytes that
have been previously challenged by foreign pathogens
or antigens and can respond rapidly and vigorously
upon reencounter with the same antigen [85]. Similarly,
memory B cells can quickly and effectively generate
antibodies upon encounter with a previously-met antigen
[86]. Thus, both memory lymphocytes play important
roles in human immune defenses. Early studies showed
that tobacco smoking apparently elevated memory T cells
(CD3+CD45RO+, CD4+CD45RO+) and class-switched
memory B cells in human peripheral blood [70, 87–89].
Active smoking in COPD patients also induced high levels
of class-switched memory B cells in blood and IgG+
memory B cells in the lung [71]. However, subsequent
ndings indicated an opposite effect of tobacco smoking
on human memory T cells. Vardavas et al [28] found a
signicant correlation of secondhand smoke with reduced
frequencies of CD3+CD45RO+ and CD4+CD45RO+
memory T cells in the blood of children, accompanying
with augmented percentages of CD3
+
and CD4
+
CD45RA
+
naive T cells. We speculate that the contradictory roles of
cigarette smoke in the circulating memory T cells of adults
and children are possibly due to immature immune system
in children, which is different from that of adult immune
system. Cigarette smoking seemed to attenuate rather than
strengthening the response of children memory T cells via
suppressing their generation.
Secondhand smoke exposure reduced effector and
memory T cells in the lungs and spleens of mice infected
with Mycobacterium tuberculosis [90], demonstrating
suppressive effects of cigarette smoke on immune
responses to infection. Further investigations showed
that in vitro pretreatments with 4-(Methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK), a major carcinogen
component of tobacco, impaired the expansion of
cytotoxic T lymphocytes (CTLs) following their transfer
into mice but elevated the frequency of precursor memory
CLTs, resulting in a nal moderate decline in memory
CLTs [91]. Moreover, acute nicotine exposure attenuated
the expansion of murine CTLs in vivo after transfer as well
as their later differentiation into memory CTLs [92].
In summary, smoking enhances T cell memory in
adult while reducing it in children. In mice, smoking also
reduces memory T cells, especially CTLs. These results
indicate that cigarette smoking exerts duel inuences on
the generation of memory T cells, perhaps depending on
an individual’s genetic background and environment.
EFFECTS OF CIGARETTE SMOKING
ON INNATE IMMUNITY
Growing evidence has indicated the positive
association of cigarette smoking with abnormality of
innate immune responses [93–95] although the potential
mechanisms are still poorly understood. Kearley et al. [96]
found that cigarette smoke exposure (CSE) elevated the IL-
33 release from epithelial cells and altered the expression
of IL-33 cognate receptor ST2 in different immune
cells. They found that smoke exposure enhanced ST2
expression by macrophages and NK cells, but diminished
it in group 2 innate lymphoid cells (ILC2s), contributing to
strengthened IL-33-dependent pro-inammatory responses
of macrophages and NK cells upon infections. These results
indicate complicated inuences of smoking on innate
immune system. Innate immune cells, including dendritic
cells (DCs), natural killer (NK) cells and macrophages etc.,
play important roles in the host defense against infections.
Effects of cigarette smoking on the innate immune cells
(Figure 1) are described below.
Smoking and toll-like receptors (TLRs)
TLRs are a class of proteins that play an essential
role in the innate immune system. They are single and
non-catalytic receptors generally expressed in innate
immune cells, including macrophages and dendritic
cells, and recognize structurally conserved molecules
that are derived from pathogens. Botelho et al. found
that CSE resulted in inammatory responses mediated
by neutrophils and monocytes, while activated CD4+ T
cells were presented in murine lungs after the prolonged
exposure, implying that innate immune cells are sufcient
to trigger the acute inammation in a response to smoke
stimulation [97]. The acute inammatory responses caused
by smoking was reported to depend on toll-like receptors
(TLRs) [98]. Furthermore, Doz and colleagues showed
that cigarette smoking (with two cigarettes twice in a
day for three days) caused acute airway inammation in
mice through TLR-4 and IL-1R1 signaling [99]. Cigarette
smoking also promoted inammatory responses and
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atherosclerosis by activating the H1R-TLR2/4-COX2
axis [100]. Study on patients with periodontitis revealed
that smoking enhanced the mRNA expression of TLR-2
and TLR-4 in the gingival tissue [101, 102]. Similarly,
increased expression of TLR-2 was observed in the lungs
of mice exposed to cigarette smoke [103]. These results
indicate that cigarette smoking induces inammation
via increasing the expression and responsiveness of
TLRs. On the other hand, it was revealed that maternal
smoking reduced the TLRs (TLR-2, TLR-3, TLR-4
and TLR-9) responsiveness of infants’ cord blood cells
compared with nonsmoking groups, possibly increasing
the risk of respiratory infections and asthma [104]. And
CSE caused a decrease in mRNA level of TLR-7 and
IRF-7 in human plasmacytoid DCs (pDC) infected by
respiratory syncytial viruses, demonstrating a suppressive
effect of cigarette smoke on pDC upon infection [105].
Taken together, cigarette smoking is likely to exacerbate
inammatory responses but attenuate immune defenses
against infections by regulating TLR signaling.
Dendritic cells (DCs)
DCs are derived from a hematopoietic lineage
of bone narrow and can induce immune responses to
pathogens via processing and presenting antigens [106].
Cigarette smoke alters the number, distribution and
development of DCs and Langerhans cells (LCs). It was
reported that active smoking correlated with augmented
numbers of DC/LC lineage and caused a dramatic increase
in the number of LCs in human alveolar parenchyma [95].
And cigarette smoking upregulated the expression of
CCR7, MHCII and CD86, and signicantly promoted the
trafcking and responses of airway DCs in mice sensitized
with OVA, facilitating the allergic airway inammation
[107]. Moreover, passive smoking enhanced the frequency
of murine pulmonary DCs and caused their accumulation
and activation, which relied on IL-1R1/IL-1α [108]. The
upregulation of DC numbers in individuals exposed to
cigarette smoke likely resulted from a rise in the cell
survival, which was supported by a previous study on
the responsiveness of human and murine DCs to smoke
exposure [109]. Thus, smoking possibly aggravates the
airway inammation through increasing both the number
and function of DCs in humans as well as mice.
Mounting evidence has indicated that cigarette
smoke or its extract also negatively regulates the function
and maturation of DCs. It was demonstrated that CSE
was signicantly associated with the reduced stimulating
capacity of DCs in mice with asthma [110], and that
murine DCs treated in vitro with carbon monoxide (CO),
a component of tobacco smoke, prevented accumulation
of pancreatic autoreactive CD8+ T cells in mice with
autoimmune diabetes [111]. Furthermore, CSE led to
the reduced pulmonary DCs and suppression of DC
maturation in murine lymph nodes, accompanying with
the decreased expression of MHC II and costimulatory
molecules (CD80 and CD86) and an attenuated capacity
of inducing T cell proliferation [112]. The smoke exposure
for a longer than 24 hours resulted in suppression of
functional development of DCs with downregulation of
MHCII, CD83, CD86 and CD40, as well as a decline
in CD45 expression on human DC cell line L428 [113].
Similar effects of cigarette smoke were reported in
human studies. The prevalence of mature DCs (CD83+)
and migratory DCs (CCR7+) was decreased while the
percentage of immature DCs (CD1a+) was obviously
increased in the lung tissues of COPD patients compared
with healthy non-smokers [114]. Moreover, smokers with
COPD had lower mRNA expression of CD83 and CCR7
than healthy non-smokers [114]. Plasmacytoid DCs were
present in tissues that were in close association with the
external environment and important for immune defenses
against viruses [115]. Cigarette smoke extract was shown
to reduce the expression of IFN-α and TLR-7 in pDC
from healthy human volunteers and in pDC infected
by respiratory syncytial virus, indicating that smoking
attenuates the antiviral function of pDC [116, 117].
In conclusion, cigarette smoking profoundly
impacts the development and function of DCs and, hence,
inammation. However, ndings concerning the impacts
of cigarette smoke on DCs are contradictory given that
smoking can either suppress or promote DC development
and function in both humans and mice. It has not been
well dened likely due to the complex compositions of
cigarette smoke, the exposure time and quantity of smoke
and the interactions between DCs and other immune cells
in animal models and humans. Further investigations are
necessary to determine the exact effects of smoking on DC
generation and function in a specic disease setting and at
a particular location.
NK cells
NK cells are similar to cytotoxic lymphocytes
expressing perforin, granzymes, TNF-α and IFN-γ [118],
and are a critical component of innate immune cells. NK
cells can rapidly and effectively respond because they also
exhibit a memory feature [119]. Motz et al. [120] assessed
the inuences of smoking on NK (CD335+) cells in
COPD mice and revealed that smoke exposure promoted
the expression of IFN-γ and CD107a in NK cells upon
stimulation, and enhanced NK cell responses. Murine NK
cells were also primed by cigarette smoke to express more
Th-17 cytokine IL-17A [121]. Meanwhile, CSE for over
four days activated CD69+ NK cells in murine lung and
induced their responses [128]. Further analysis of human
data showed that smokers with or without COPD had an
increase in the frequency of circulating NK (CD56+CD3-)
cells compared with former smokers with COPD and
healthy nonsmokers [122, 123]. On the other hand,
previous investigations also demonstrated an obvious
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reduction of NK (CD16+) cells in the peripheral blood of
healthy smokers and the smokers exposed occupationally
to organic solvents compared with nonsmokers [124, 125].
Cigarette smoke was reported to suppress the expression
of IFN-γ and TNF-α in human NK (CD56+CD3-) cells
stimulated by poly I:C while smoking-conditioned
medium (SCM) reduced the cytotoxicity of NK cells that
had a lower perforin production [126, 127]. Similarly,
Mian et al. found that cigarette smoke apparently
attenuated the activation and cytolytic capacity of human
NK cells with decreased expression of activation marker
CD69 [128].
Taken together, smoking still exerts dual effects on
the frequency and function of NK cells in both mice and
humans. The actual inuences of cigarette smoking on NK
cells may vary, depending on the differential pathological
conditions or disease settings and subsets of NK cells with
different surface markers. Different subsets of NK cells
may paradoxically respond to cigarette smoke in a given
setting at a given time.
Macrophages
Macrophages respond to exogenous pathogens
via phagocytosis and digestion, and recruit/activate
lymphocytes via their antigen-presenting ability
[129]. Ko and others reported that both smoking and
nicotine treatments could enhance the expression of
proinammatory chemokine IL-8 in macrophages of both
humans and mice [130–132]. Metcalfe et al [133] found
that cigarette smoke extract inhibited the responses of
COPD-derived alveolar macrophages to TLR signaling
and Haemophilus inuenza stimulation. These results
indicated that smoke-treated human macrophages
and IL-8 produced by these macrophages facilitated
inammation, although studies on murine macrophages
demonstrated that smoking remarkably suppressed the
phagocytosis of macrophages and enhanced bacterial
survival [134]. Another report showed a similar trend
in phagocytic function of human macrophages THP-
1 treated with cigarette smoke extract [135], with an
increase in M2 macrophages. M2 macrophage is regarded
as a subset of anti-inammatory cells that can attenuate
inammation, whereas M1 macrophage is referred to as
pro-inammatory cells [136]. Finally, it was found that
bone marrow-derived mast cells exposed to cigarette
smoke promoted the polarization of murine macrophages
into M2 subset [137].
In summary, smoke treatments stimulate human
macrophages to release IL-8, facilitating inammation
rather than directly enhancing their function while
cigarette smoking suppresses the phagocytosis of
murine macrophages. However, smoking promotes M2
polarization of both human and murine macrophages.
Further studies are needed to fully understand impacts of
smoking on the function of macrophages, especially in
humans.
MOLECULAR MECHANISMS
UNDERLYING SMOKING-ASSOCIATED
IMMUNOPATHOLOGY
Cigarette smoke is an important source of hazardous
chemicals, including nicotine, reactive nitrogen species
(RNS), reactive oxygen species (ROS), free radicals, nicotine
and polycyclic aromatic hydrocarbons. They cause oxidative
stress, DNA damage, inammation and various cancers [3,
138, 139]. The molecular mechanisms behind the smoking-
induced effects on immune cells are still poorly understood.
Early investigation revealed that cigarette smoke initiated
the MAPK signaling pathways, which in turn regulated the
activation of transcription factors (TFs) and affected DNA-
binding capacity of more than 20 TFs, including nuclear
factor-kappa B (NFκB) [140]. The functional alterations
of TFs contributed to transcriptional changes of their target
genes, including inammatory cytokines and chemokines.
Furthermore, nicotine was also reported to exert anti-
inammatory effects on activated immune cells via nicotinic
acetylcholine receptors (nAChRs) mediated molecular
pathways. Nevertheless, the exact molecular mechanisms
underlying smoking-associated immunopathology remain
largely unknown.
NFκB
Activation of NFκB with oxidative stress plays a key
role in inammation [141]. It was reported that cigarette
smoke induced degradation of IκB-α and activation of
nuclear factor-kappa B (NFκB) in lymphocytes and
other types of cells, resulting in increased expression of
cyclooxygenase-2 and iNOS [142, 143]. An analysis using
protein/DNA array showed that CSE strengthened the
transcriptional activity of NFκB via promoting its nuclear
translocation and DNA binding activity in human A549 cells
[140]. Lerner et al [144] demonstrated that cigarette smoke
facilitated the expression of cytokine IL-8 and attenuated
differentiation of human monocytes via activating NFκB
pathway. Furthermore, Reynolds and colleagues found that
CSE enhanced the activation of Ras and NFκB, and that
downregulation of the receptor for advanced glycation end-
product (RAGE) resulted in the reduced activation of NFκB
in alveolar epithelial cells [145]. Thus, it was suggested that
cigarette smoke stimulated alveolar epithelial cells to express
more cytokine IL-1β and chemokine CCL5 via RAGE-
mediated Ras-NFκB pathway, possibly contributing to
leukocyte recruitments. On the contrary, others demonstrated
that CSE suppressed the activation of NFκB in human
and murine tracheobronchial epithelial cells infected by
Haemophilus inuenza (H. inuenza), and these ndings
were supported by a study using animals infected with
H. inuenza [146]. Mian et al. also observed that smoke-
conditioned media signicantly suppressed the activation
of NFκB and IRF-3 in nonsmokers’ PBMCs treated with
poly I:C [147], while cigarette smoke extract was shown
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to dramatically elevate the DNA binding activity of AP-1
rather than NFκB in endothelial cells of human umbilical
core vein [148].
Taken together, previous studies indicate smoking
also exerts dual roles in regulating NFκB activation in
both humans and animals. The net effects of cigarette
smoking on NFκB activity differ widely, depending on
cell types and extracellular environment with or without
exogenous pathogens, which possibly contributes to a
decline in immunity against bacterial infections but an
increase in pulmonary inammation.
ERK
There are three major types of MAP Kinase
pathways, including ERK1/2, JNK/SAPK and p38
pathways [149]. Iles et al. found that 4-hydroxynonenal
(HNE) induced by cigarette smoke in pulmonary epithelial
cells enhanced the phosphorylation of ERK, JNK and
c-Jun and the binding capacity of AP-1 with upregulation
of Heme oxygenase-1 (HO-1) [150]. Similar ERK-c-Jun
pathway induced by CSE was reported by others. Li et al.
[151] revealed that CSE induced ERK phosphorylation,
which in turn phosphorylated c-Jun in smooth muscle
cells, contributing to cyclin D1 upregulation. They also
demonstrated the involvement of MEK/ERK1/2 MAPK
pathway in the diminished expression of cystic brosis
transmembrane conductance regulator (CFTR) induced by
cigarette smoke in human bronchial epithelial cells [152].
In addition to acting on epithelial cells and smooth muscle
cells, CSE treatments also enhanced ERK phosphorylation
and suppressed IL-12p70 expression in mature DCs, while
the ERK phosphorylation in turn increased nuclear TF
c-Fos, leading to the reduction in IL-23 protein levels
[153]. It remains to be dened whether cigarette smoke
affects ERK phosphorylation in adaptive immune cells.
P38 MAPK
Both in vitro and animal studies have shown that
cigarette smoke exposure (CSE) exerts its effects through
p38 MAPK signaling pathway. It was reported that CSE
apparently elevated the phosphorylation of p38 MAPK
in mice with smoke-induced pulmonary inammation
[154, 155]. Furthermore, Moretto et al. [156] found that
CSE enhanced both mRNA and protein expression of
IL-8, which was important for neutrophil chemotaxis,
accompanying with phosphorylation of p38 MAPK
and MEK2 in human pulmonary cells. Treatments with
inhibitors of p38 MAPK or MEK2 accelerated the
degradation of IL-8 mRNA. Thus, they suggested that
cigarette smoking augments IL-8 expression in pulmonary
structural cells through p38 MAPK/MEK pathway,
resulting in neutrophil recruitments into the lungs and
inammatory sites. Additionally, some investigations [157,
158] demonstrated that both p38 MAPK and ERK1/2
pathways were concurrently implicated in the secretion
of IL-8 and pulmonary inammation induced by cigarette
smoking.
In conclusion, tobacco smoking activates MAPK
signaling in both murine and human pulmonary resident
cells and leukocytes, and hence induces the expression of
proinammatory cytokines such as IL-8.
Histone modication
In addition to effects on NFκB and MAPK
signaling pathways, tobacco smoke also alters the cellular
chromatin via histone modication [159]. Previous studies
established an association of tobacco smoking with
augmented acetylation of histone 4 and phosphorylated-
histone 3 in human and mice [154, 160]. Yang et al.
[161] revealed that CSE attenuated the activity of histone
deacetylase (HDAC) and reduced the production of
HDAC1, HDAC2, and HDAC3 in human macrophages.
Furthermore, expression of SIRT1, a type of histone/
protein deacetylases [162], was suppressed by cigarette
smoke in inammatory cells of murine lungs as well
as macrophage cell lines, resulting in abrogation of the
interaction of SIRT1 with RelA/p65 and acceleration of
RelA/p65 acetylation [163]. Since chromatin structures
regulated by histone acetylation and deacetylation affected
gene transcriptions [164], smoke-induced alterations
in histone modication could lead to aberrant gene
transcriptions in various immune cells. Taken together,
smoking alters the cellular chromatin of both murine and
human macrophages via histone modication.
Impacts of nicotine on molecular signaling
pathways
Nicotine has been shown to be an
immunosuppressive agent that can modulate innate and
adaptive immune responses [165, 166] through interacting
with nAChRs on the surface of immune cells, including
macrophages, T and B lymphocytes [167]. Recently,
considerable work has been done to show that α7 nAChR,
one type of nAChRs, plays a crucial role in nicotine’s
anti-inammatory effects. The activation of α7 nAChR
by nicotine in murine macrophages interacted with
Jak2 and then induced the phosphorylation of STAT3,
which subsequently inhibited the transcription of pro-
inammatory cytokines [168]. Furthermore, activated
α7 nAChR suppressed the phosphorylation of IκB in
human monocytes, resulting in inhibition of nuclear
translocation of NFκB [166, 169]. Besides, nicotine
may regulate additional signaling pathways beyond
activation of nAChRs. Early studies showed that nicotine
facilitated the release of alpha-melanocyte-stimulating
hormone (alpha-MSH) in frog melanotrophs through
inducing inositolphospholipid breakdown and increasing
the intracellular Ca(2+) concentration, indicating the
involvement of non-cholinergic nicotine receptor in
nicotine mediated effects [170]. It was also reported
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that nicotine treatment enhanced Ca(2+) channels and
suppressed nitric oxide (NO) signaling pathways in
smooth muscle cells of rats [171]. Moreover, interleukin-1
receptor-associated kinase M (IRAK-M), a negative
regulator of innate TLR-mediated immunity, was involved
in the anti-inammatory effects of nicotine through α7
nicotinic receptor in human macrophages [172]. Although
the major evidence has revealed that nicotine functions via
both nAChRs and non-nAChRs in immune cells, the exact
signaling pathways of nicotine are still largely unclear and
more studies are required to fully explore its molecular
mechanisms.
CONCLUSION
Ample evidence has shown that both innate
immunity and adaptive immunity are susceptible to
cigarette smoke, which interrupts immunological
homeostasis, causes various diseases, and exerts
paradoxical effects on immune and tissue cells through
regulating NFκB and MAPK signaling as well as histone
modication. In particular, cigarette smoke acts as a
double-edged sword that either exacerbates pathological
immune responses or attenuates the normal defensive
function of the immune system, possibly owing to the
complexities and functional diversities of cigarette
smoke components and individuals’ medical condition.
Nevertheless, smoking plays a harmful rather than
benecial role in either case. Perhaps, tobacco smoke
manufactured from different parts of the country may
differ in actual chemical components. It is unknown why
smoking is always deleterious rather than benecial,
even though it exerts dual effects on immune responses.
For instance, cigarette smoke generally weakens
immunity against infections but paradoxically promotes
autoimmunity. We speculate that the weakened immunity
with prolonged chronic infection results in cross-reactive
autoimmunity against both a pathogen and cross-reactive
self-tissue. It is also possible that cigarette smoke exerts
differential effects on immunity in the context of various
regional immunopathology and diseases. Although
previous studies have revealed some of the cellular and
molecular mechanisms responsible for immunoregulation
induced by cigarette smoke, the exact mechanisms
underlying smoking-associated immunopathology remain
mostly unclear, which warrants further investigations.
CONFLICTS OF INTEREST
The authors declare that there is no any conict of
interest in this review.
GRANT SUPPORT
This study was partially supported by a grant from
National Natural Science Foundation of China (NSFC
81471550).
Author contributions
FQ, CLL, and HL prepared the literature and wrote
the manuscript; YQZ, SZH and SH prepared the literature;
XL and ZD edited the manuscript.
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