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Autophagy and inflammation



Autophagy is a homeostatic mechanism involved in the disposal of damaged organelles, denatured proteins as well as invaded pathogens through a lysosomal degradation pathway. Recently, increasing evidences have demonstrated its role in both innate and adaptive immunity, and thereby influence the pathogenesis of inflammatory diseases. The detection of autophagy machinery facilitated the measurement of autophagy during physiological and pathophysiological processes. Autophagy plays critical roles in inflammation through influencing the development, homeostasis and survival of inflammatory cells, including macrophages, neutrophils and lymphocytes; effecting the transcription, processing and secretion of a number of cytokines, as well as being regulated by cytokines. Recently, autophagy-dependent mechanisms have been studied in the pathogenesis of several inflammatory diseases, including infectious diseases, Crohn’s disease, cystic fibrosis, pulmonary hypertension, chronic obstructive pulmonary diseases and so on. These studies suggested that modulation of autophagy might lead to therapeutic interventions for diseases associated with inflammation. Here we highlight recent advances in investigating the roles of autophagy in inflammation as well as inflammatory diseases.
Qian et al. Clin Trans Med (2017) 6:24
DOI 10.1186/s40169-017-0154-5
Autophagy andinammation
Mengjia Qian, Xiaocong Fang and Xiangdong Wang*
Autophagy is a homeostatic mechanism involved in the disposal of damaged organelles, denatured proteins as well
as invaded pathogens through a lysosomal degradation pathway. Recently, increasing evidences have demonstrated
its role in both innate and adaptive immunity, and thereby influence the pathogenesis of inflammatory diseases. The
detection of autophagy machinery facilitated the measurement of autophagy during physiological and pathophysi-
ological processes. Autophagy plays critical roles in inflammation through influencing the development, homeostasis
and survival of inflammatory cells, including macrophages, neutrophils and lymphocytes; effecting the transcription,
processing and secretion of a number of cytokines, as well as being regulated by cytokines. Recently, autophagy-
dependent mechanisms have been studied in the pathogenesis of several inflammatory diseases, including infectious
diseases, Crohn’s disease, cystic fibrosis, pulmonary hypertension, chronic obstructive pulmonary diseases and so on.
These studies suggested that modulation of autophagy might lead to therapeutic interventions for diseases associ-
ated with inflammation. Here we highlight recent advances in investigating the roles of autophagy in inflammation as
well as inflammatory diseases.
Keywords: Autophagy, Inflammation, Inflammatory diseases
© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(, which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Autophagy is a cellular process for the disposal of dam-
aged organelles, denatured proteins as well as invaded
pathogens through a lysosomal degradation pathway
[1]. It was demonstrated to be activated during starva-
tion or other stress response, including hypoxia, reac-
tive oxygen species, DNA damage, protein aggregates,
damaged organelles or intracellular pathogens. rough
autophagy, cells can eliminate damaged or harmful com-
ponents, thus it allows cells to survive in response to
multiple stressors [2]. Autophagy has been implicated in
a number of fundamental biological processes, including
aging, immunity, development, and differentiation [3].
Besides autophagy, the cellular response to stress
involves numerous other pathways, of which, the most
common and important is inflammation. Inflamma-
tion plays protective or destructive roles in the response
to endogenous or exogenous irritation or injury. It can
be provoked by physical, chemical and biologic agents,
including mechanical trauma, exposure to excessive
amounts of sunlight, x-rays and radioactive materials,
corrosive chemicals, extremes of heat and cold, or by
infectious agents such as bacteria, viruses, and other path-
ogenic microorganisms. e pathogenesis of inflammation
includes hemodynamic changes, leukocytes exudation,
release of chemical mediators and hormonal response [4].
ere are increasing evidences suggesting that
autophagy plays critical role in the development and
pathogenesis of inflammation and immunity response
[5]. e autophagy machinery interfaces not only
with most cellular stress-response pathways, but also
entails direct interaction between autophagy proteins
and immune signaling molecules [6]. e relationship
between autophagy and inflammation is complex, both
inductive and suppressive.
In this review, we summarized recent studies in
autophagy and inflammation, and discussed the func-
tions of the autophagy pathway and the autophagy pro-
teins in inflammation and inflammatory diseases.
Autophagy biology
Concept understanding
Autophagy is a general term for pathways by which cyto-
plasmic material, including soluble macromolecules and
Open Access
Zhongshan Hospital Institute of Clinical Science, Shanghai Institute
of Clinical Bioinformatics, Fudan University Medical School, Shanghai,
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Qian et al. Clin Trans Med (2017) 6:24
organelles, is delivered to lysosomes for degradation. ere
are at least three different types of autophagy, including
macroautophagy, chaperone-mediated autophagy and
microautophagy [2]. Autophagy not only enables the reuse
of intracellular constituents and supplies an amino acid
pool during periods of starvation and stress response, but
also helps to eliminate old/damaged organelles and extra-
cellular organisms, thus provides basic cellular homeo-
stasis. In addition, it was reported to play important roles
in multiple pathophysiological processes including devel-
opment, aging, and degeneration. Aberrant regulation
of autophagy may result many diseases such as cancer
[7], neurodegenerative diseases [8], and myopathies [9].
Recently, autophagy was found to be involved in immunity
[5]. It can act as a direct effector by eliminating invading
pathogens, regulating innate pathogen recognition, con-
tributing to antigen presentation via major histocompat-
ibility complex (MHC) class II molecules, and controlling
B- and T cell development.
Molecular regulation
One breakthrough of the molecular mechanism for
autophagy was achieved by identifying the genes in yeast,
which are termed as autophagy-related genes (ATG) [10,
11]. ese core Atg proteins are composed of four sub-
groups: (1) e Atg1/unc-51-like kinase (ULK) complex,
which regulate the initiation of autophagy; (2) two ubiq-
uitin-like protein [Atg12 and Atg8/microtubule-asso-
ciated protein light chain 3 (LC3)] conjugation systems,
which assist the elongation of the autophagic membrane;
(3) the class III phosphatidylinositol 3-kinase (PI3K)/
Vps34 complex I, which participate at the early stage of
the autophagosome membrane formation; and (4) two
transmembrane proteins, Atg9/mAtg9 (and associated
proteins involved in its movement such as Atg18/WIPI-
1) and VMP1, which may contributes to the delivery of
membrane to the forming autophagosome [12]. e
process of autophagy involves two major steps: induc-
tion of autophagosome and fusion of autophagosome
with lysosome (Fig. 1). e ULK/Atg1 kinase complex,
the autophagy-specific PI3-kinase complex, and PI(3)P
effectors and their related proteins are important for the
nucleation step, whereas the Atg12- and LC3/Atg8-con-
jugation systems are important for the elongation step.
Given this strong association between autophagy and dif-
ferent physiological and pathophysiological processes,
there is a rapidly growing need among scientists to be
able to accurately detect autophagy and to study its func-
tion. Details of the autophagy measurement methods
have been reviewed elsewhere [13, 14]. For example, the
number of autophagosome can be measured through
electron microscopy, which is the most traditional and
straightforward method [15]. However, the technique
requires considerable specialized expertise since it is
not easy to distinguish autolysosomes from endocytic
compartments or from other vacuoles/structures once
autophagosomes degradation processed. Immuno-gold
labeling on ultrathin cryosections is a favorable approach
to visualize autophagic structures, while specific antibod-
ies that work properly with aldehyde fixation and the fra-
gility of the autophagic structures are required, as well as
the ultrathin cryosections techniques.
To fully understand a given biological process, it
is usually critical to perform experiments to modu-
late the activity of the process. e autophagic activity
can be inhibited or activated with agents that regulate
autophagosome formation or subsequent degradation
steps. However, right now we still lack highly specific
autophagy inhibitors and activators. One of the most
commonly used inhibitors is PI3-kinase inhibitors,
including wortmannin, LY294002, or 3-methyladenine
(3-MA). However, all of them are not autophagy specific
and can meantime influence other cellular processes [16].
Another consideration for more specific inhibition of
the autophagy pathway is to knockout or knockdown of
different Atg genes, which has been reported in several
studies [17, 18] and it is more specific than pharmaco-
logical agents. However even present at very low levels,
some Atg proteins still function normally in autophagy,
which may affect the experiment results and conclu-
sions [19]. us, it is recommended that investigator
not only confirm effective knockdown of autophagy pro-
tein expression levels with each siRNA, but also confirm
effective inhibition of the autophagy pathway using a
known autophagy-inducing stimulus such as starvation.
Given these potential limitations for each measure-
ment, it is vital to state that none of these assays can be
used alone to monitor or modulate cellular autophagic
activity. In order to understand the effects of autophagy
in a given biological settings, it is absolutely necessary
to carry out multiple assays and compare the results of
these investigations as a whole.
Autophagy ininammation
A complex association has been identified between
autophagy and inflammation. First, autophagy influences
the development, homeostasis and survival of inflamma-
tory cells, including macrophages, neutrophils and lym-
phocytes, which play critical roles in the development
and pathogenesis of inflammation (Fig.2).
Macrophage is essential for the host defense system. As a
kind of phagocytes, it is able to uptake and kill pathogens
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Qian et al. Clin Trans Med (2017) 6:24
intracellularly as well as producing inflammatory
cytokine and chemokines [20]. Studies have shown that
macrophages lacking Atg16L1 or Atg7, essential compo-
nents of the autophagic machinery, appealed enhanced
production of interleukin (IL)-1β and IL-18 in response
to inflammatory stimulation through toll-like receptor
(TLR) 3/4 signal pathway. Besides, the TLR signaling can
also enhance phagosome maturation and the fusion of
phagosomes and lysosomes depending on the autophagy
pathway proteins ATG5 and ATG7, leading to rapid acid-
ification and enhanced killing of the ingested organism
in macrophages/monocytes [21, 22]. In mice, knockout
of autophagy protein Atg5 in macrophages and neutro-
phils increases susceptibility to infection with L. mono-
cytogenes and the protozoan T. gondii. Atg5 was required
for interferon (IFN)-γ/LPS-induced damage to the T.
gondii parasitophorous vacuole membrane thus killing
intracellular pathogens via autophagosome-independent
process [23]. Recent studies have shown that autophagy
contributed to the execution of caspase-independent cell
death in activated macrophages. e study detected an
increase in poly (ADP-ribose) polymerase activation and
reactive oxygen species (ROS) production in lipopolysac-
charide +Z-VAD (a pan caspase inhibitor)—treated mac-
rophages, followed by the formation of autophagic bodies
and macrophage cell death. e death of activated mac-
rophages could also be beneficial in controlling the level
of inflammation [24].
Neutrophils are multifunctional cells, playing a cen-
tral role in the innate immune system [25]. Inflamma-
tory stimuli attract neutrophils to infected tissues where
they engulf and inactivate microorganisms through the
Fig. 1 Induction and mechanisms of autophagy in mammalian cells. The process of autophagy involves two major steps: induction of autophago-
some and fusion of autophagosome with lysosome. The ULK/Atg1 kinase complex, the autophagy-specific PI3-kinase complex, and PI(3)P effectors
and their related proteins are important for the nucleation step, whereas the Atg12- and LC3/Atg8-conjugation systems are important for the
elongation step. In addition, other proteins required for autophagosome-lysosomal fusion, lysosomal acidification, and lysosomal digestion, and
regulatory signals that integrate environmental cues with the autophagic machinery are involved in autophagy
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Qian et al. Clin Trans Med (2017) 6:24
fusion of phagosomes with granules and the formation
of phagolysosomes, in which antimicrobial peptides and
ROS act synergistically for the clearance of pathogens
[26]. In addition, neutrophil activation, degranulation
and release of ROS into the extracellular medium, will
lead to host tissue injury [27], while neutrophil apoptosis
contributes to the resolution of inflammation [28]. ere
is evidence that autophagy occurs in neutrophils in both
phagocytosis-independent and phagocytosis-dependent
manner similar to that in macrophages [29]. However, the
detailed mechanisms are not completely elucidated. So
far, most of the studies focused on the role of autophagy
in neutrophil death.
Recent studies have demonstrated that adhesion mol-
ecules induced autophagy-associated caspase-inde-
pendent cell death in neutrophils, characterized by large
cytoplasmic vacuolization and organelle fusion [30]. Such
vacuolized neutrophils were observed in septic shock,
cystic fibrosis, rheumatoid arthritis and several skin
diseases [31], suggesting that induction of autophagy
in these cells is a general phenomenon of neutrophilic
inflammation response. Besides, neutrophil extracellular
traps cell death (also named NETosis), is another type of
programed cell death in neutrophils and involve NADPH
oxidase activity. Recent studies have shown that inhibi-
tion of autophagy prevented NETosis via preventing
intracellular chromatin decondensation, thus resulting in
cell death characterized by hallmarks of apoptosis [32].
Apart from innate immunity, autophagy also plays an
indispensable role in adaptive immunity, including the
development and homeostasis of the immune system
and antigen presentation [33]. Several tissue-specific
knockout models have been developed during the past
few years to study the role of autophagy in T lympho-
cytes [34]. T cell receptor (TCR) activation is a strong
trigger for autophagy in T lymphocytes. Meantime,
Fig. 2 Effects of autophagy in inflammatory cells. Autophagy influences the development, homeostasis and survival of inflammatory cells, includ-
ing macrophages, neutrophils and T lymphocytes and B lymphocytes
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Qian et al. Clin Trans Med (2017) 6:24
autophagy-related genes are required for T cell prolifera-
tion upon TCR stimulation. T lymphocytes lacking Atg5,
Atg7, Atg3 or Beclin-1 all showed impaired proliferation
and enhanced cell death. e deficiency of Atg5 gene
leads to the reduction of thymic cellularity and decreased
number of peripheral T lymphocytes through enhanc-
ing cell death, suggesting the role of autophagic proteins
in the regulation of T cell homeostasis [35]. Besides,
autophagy also plays an important role in the selection
and function of thymocytes. Studies have demonstrated
that Atg5-deficient thymic epithelial cells underwent
a disrupted process of positive and negative selection;
moreover, when these cells transferred, they are apt to
induce autoimmune diseases [36]. Via selectively degrad-
ing mitochondria [14] and endoplasmic reticulum [37],
autophagy helps to maintain intracellular organelle
homeostasis. Atg5-deficient T lymphocytes revealed a
remarkable enrichment of the content of mitochondria,
which was assumed to be the major reservoir of toxic
reactive oxygen species [38]. Although it is demonstrated
that autophagy is required for T cell survival, excessive
autophagy seems to be destructive for T lymphocytes.
Besides, autophagy is differentially regulated in each T
helper subset. For example, 2 cells are more resistant
to growth factor-withdrawal cell death when autophagy
is blocked [39]. Moreover, TCR-induced autophagy is
compromised in aged CD4+ T lymphocytes while the
mechanisms have been unclear [40].
Besides the indirect effects on the survival and func-
tion of T cells through autophagic proteins, autophagy
also showed a direct role in antigen presentation to anti-
gen-specific T cells (a process essential for the induc-
tion of acquired immunity) [41]. MHC class II molecules
are localized on autophagosomes, and the autophagic
machinery promotes the presentation of viral and self-
antigens by MHC class II molecules to antigen-specific
CD4+ T cells [42]. Upon infection by human simplex
virus 1, autophagy controls the MHC class I-dependent
presentation of viral antigens to CD8+ T cells [43].
Studies of autophagy in B lymphocytes are fewer than
that in T lymphocytes. However, present studies on the
role of autophagy in B lymphocytes have raised many
interest and important questions for further investiga-
tion. As in T cells, Atg5 gene is also required in the devel-
opment and survival of B lymphocytes. However, there is
a study shown that Atg5 was only required for the main-
tenance of B-1a B cells, but not B-1b or B-2 B cells, and
affected the number of pre-B but not pro-B cells [44],
which suggested that Atg5 genes may play a critical role
in the specific stages of B cell differentiation. Analysis
of the expression of a Beclin 1-GFP transgene in T and
B cells suggests that Beclin 1 may be involved in the
development of lymphocytes and provides a critical link
between apoptosis and autophagy. Beclin 1-chimeras had
greatly reduced numbers of early B cells in the bone mar-
row compared with controls, while the peripheral B cell
compartment was normal [45]. Recent studies indicated
that autophagy was induced specifically by apoptotic B
cell antigen receptor signaling [46].
Autophagy andproduction ofinammatory
Regulation ofautophagy bycytokines
Autophagic proteins have important roles in the regula-
tion of inflammatory mediators and will affect cytokine
production in macrophages [47]. In fact, it is well estab-
lished that 1 cytokines, including IFN-γ, TNF-α,
IL-1, IL-2, IL-6 and TGF-β, have been shown to have
the effects of autophagy inducement, while the classi-
cal 2 cytokines, including IL-4, IL-10 and IL-13, have
the effects of inhibition [48, 49]. Activation of mac-
rophages with IFN-γ leads to the increased maturation
of mycobacteria-containing phagosomes and autophagy
in an Irgm1/IRGM-dependent manner [50], leading to
increased intracellular killing of pathogens. However,
IFN-γ-induced phagosome maturation can be abrogated
by TNF blockers, which suggested that IFN-γ-induced
phagosome maturation and autophagy might be TNF-α
dependent. Interestingly, TNF-α is also demonstrated
to play a role in stimulating autophagy in various cell
types, while the actions and mechanisms are different
between various cell types [51, 52]. For example, TNF-α
can up-regulate the expression of the autophagy genes
LC3 and Beclin 1 through activation of the Jun kinase
signaling pathway as well as the inhibition of Akt acti-
vation [53]. TNF-α can also induct autophagy through
ERK1/2 pathway [54, 55], while activation of NF-κB can
inhibit TNF-α-induced autophagy, which is dependent
on the generation of ROS [56]. On the contrary, studies
have shown that the 2 cytokines, like IL-4, IL-13 and
IL-10, could inhibit starvation- or inflammatory stimu-
lation-induced autophagy through different pathways.
Inhibition of starvation-induced autophagy is depend-
ent on the Akt pathway, while inhibition of IFN-γ or
rapamycin-induced autophagy is dependent on STAT
signaling pathway [57, 58]. In addition, other cytokines,
chemokines and growth factors have also been impli-
cated in the regulation of autophagy. TGF-β has been
shown to induce autophagosome formation and can
increase expression of autophagic mRNA, including
Atg5, Atg7 [59]. However, the CC chemokine CCL2
(monocyte chemoattractant protein-1) and IL-6 both
can stimulate autophagy and up-regulate anti-apoptotic
proteins [60]. Moreover, IL-1 has also been demon-
strated to stimulate autophagy [61]. However, insulin-
like growth factor 1 [62] and fibroblast growth factor
Page 6 of 11
Qian et al. Clin Trans Med (2017) 6:24
2 [63] both can inhibit autophagy, while the detailed
mechanisms still need to be further studied.
Regulation ofcytokines byautophagy
Autophagy can affect the secretion of cytokines by itself
(Fig. 3). Autophagy regulates IL-1β secretion through
at least two separate mechanisms. Loss of autophagy in
macrophages or dendritic cells, either through knock
down of Atg7, Atg16L1 or Beclin 1, or by treatment
with the autophagy inhibitor 3-MA, stimulates the
processing and secretion of IL-1β in response to TLR
agonists [64]. is effect may be dependent on TIR-
domain-containing adaptor-inducing IFN-β (TRIF) and
mitochondrial ROS and/or mitochondrial DNA and at
least partially dependent on NLRP3 [65], and also may
be independent of TRIF, but dependent on p38 MAPK
signaling [66]. Conversely, induction of autophagy with
rapamycin inhibits the secretion of IL-1β in murine
dendritic cells in response to LPS with ATP or alum.
Given that IL-1α and IL-1β have both been shown to
induce autophagy, this may act as a negative feedback
loop to control IL-1-induced inflammation. Similarly,
the secretion of IL-18, IL-6 and TNF-α was also regu-
lated by autophagy. Inhibition of autophagy enhanced
the production of IL-18, but reduced the production of
IL-6, IL-8 and TNF-α [67].
e modulation of autophagy in the secretion of IFN in
virally-infected cells is controversial. Atg5 or autophagy
deficient plasmacytoid dendritic cells was failed to pro-
duce IFN-α in response to infection with vesicular sto-
matitis virus (VSV) [68]. In contrast, other studies have
demonstrated that embryonic fibroblasts from Atg5-/-
mice are more resistant to VSV infection and produce
higher levels of IFN-a and IFN-b mRNA in response to
VSV or stimulation with dsRNA [poly(I:C)], compared
with WT controls [69]. In hepatitis C virus infected
hepatocytes, Atg7 knockdown induced IFN signal path-
way, thus induced cell death [70, 71].
Fig. 3 The interactions of autophagy and inflammatory cytokines or chemokines. Autophagy can affect the secretion of cytokines by itself, includ-
ing Th1 cytokines, IFN-γ, TNF-α, IL-1, IL-2, IL-6, TGF-β, MCP-1 and Th2 cytokines, IL-4, IL-10 and IL-13, as well as other cytokines, IL-1β, IL-18, IFN-a, IFN-β,
Page 7 of 11
Qian et al. Clin Trans Med (2017) 6:24
Autophagy inacute andchronic inammatory
Recently, emerging evidences have indicated that the
process of autophagy may play an essential role in acute
and chronic inflammatory processes, and thereby poten-
tially impact the outcome of disease progression.
Crohn’s disease
Crohn’s disease (CD) is a chronic and sometimes debili-
tating form of inflammatory bowel disease characterized
by inflammation, ulceration, and neutrophil influx in
the intestinal epithelia [72]. e underlying cause of CD
is unknown; however it is clear that both environmen-
tal and genetic factors are required for its development.
Recent studies have found links between autophagy
related genes such as ATG16L, NOD2 and immunity-
related p47 guanosine triphosphatase (IRGM) and the
pathogenesis of CD through bioinformatics.
Nod2, a protein of the NLR family, functions as an
intracellular bacteria sensor and was required in the
induction of autophagy by bacterial peptidoglycan cell
wall in intestinal epithelial cells [73]. ree major NOD2
variants are associated with CD; two missense muta-
tions, R702W and G908R, and one frameshift muta-
tion, L1007fsinsC. Human studies suggest that these
NOD2 variants result in a loss of function [74]. A T300A
variant in the ATG16lL gene, which plays a key role in
autophagosome formation, has been identified as an
associated risk factor for CD [75]. Another genome-wide
association study suggested variants in the gene encod-
ing IRGM were associated with CD [76]. Studies revealed
variants of these genes may have been associated with
the impaired clearance of harmful bacterial species asso-
ciated with CD, impaired antigen presentation, and also
with the higher production of proinflammatory cytokines
implicated in the pathogenesis of CD, while further stud-
ies are still warranted to examine the contribution of
these genes in the pathogenesis and treatment of CD.
Infectious disease
Autophagy can exert anti-bacterial and anti-pathogen
functions, which have already been demonstrated in sev-
eral infectious diseases [77]. Take the case of Mycobacte-
rium tuberculosis infection, the autophagy pathway and/
or autophagy proteins have a crucial role in resistance
to bacterial, viral and protozoan infection in metazoan
organisms. Mycobacterium tuberculosis is an intracellular
pathogen persisting within phagosomes through interfer-
ence with phagolysosome biogenesis [78]; while experi-
mental stimulation of autophagy can overcome the
trafficking block imposed by M. tuberculosis [79]. Con-
versely, chemical inhibitors of autophagy will promote
infection [80]. Additional studies have implicated the role
of autophagy in defense against other microbial patho-
gens, such as Legionella pneumophila [81], Dictyostelium
discoideum [82], Shigella [83] and so on.
Pulmonary hypertension
Pulmonary arterial hypertension (PAH) is a complex dis-
ease of varying etiologies which characterized mainly by
vasoconstriction, increased pulmonary artery pressure,
thickening and fibrosis of the artery [84]. Recent stud-
ies have examined the prospective role of autophagic
proteins in experimental models of PAH. Exposure to
chronic hypoxia in mice resulted in the increased expres-
sion of LC3B and its conversion of LC3B-II in the lung.
Increased LC3B staining was also observed in small
pulmonary vessels of animals subjected to hypoxia.
Moreover, hypoxic lungs contained elevated numbers of
autophagosomes, as detected by electron microscopy.
Importantly, mice genetically deleted for LC3B (LC3B-/-)
displayed increased indices of pulmonary hypertension,
including increased right ventricular systolic pres-
sure, and Fulton’s index relative to wild-type mice, after
chronic hypoxia [85]. LC3 exerts protective effects in the
pathogenesis of PAH through hypoxia-specific inhibitory
effects on the parameters involved in proliferative sign-
aling (MAPK3/ERK1–MAPK1/ERK2 activation, VEGF
secretion), as well as the inhibitory effects on pulmonary
artery endothelial cells proliferation [86, 87].
Cystic brosis
e pathological features of cystic fibrosis (CF) include
aberrant accumulation of hyperviscous mucous in the
airways, impaired mucociliary clearance, and increased
inflammation partly due to the mutation of cystic fibro-
sis transmembrane conductance regulator (CFTR) [88].
Recent studies have demonstrated that human airway
epithelial cells from CF patients, which bear the mutation
in the CFTR gene, have an impaired autophagic response.
Defective CFTR-induced upregulation of ROS and tis-
sue transglutaminase drive the crosslinking of Beclin 1,
leading to sequestration of PI3-K complex III and accu-
mulation of p62 [89], which regulates aggresomal forma-
tion. Both CFTR knockdown and the overexpression of
GFP-tagged-CFTRF508del induce Beclin 1 downregula-
tion and defective autophagy in non-CF airway epithelia
through the ROS-tissue transglutaminase pathway [90].
ese data linked the CFTR defect to autophagy defi-
ciency, leading to the accumulation of protein aggregates
and to lung inflammation.
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a
chronic airway inflammatory disease characterized by
progressive deterioration of lung function [91, 92]. More
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Qian et al. Clin Trans Med (2017) 6:24
and more evidences have demonstrated that macroau-
tophagy plays a significant and complex role in COPD
pathogenesis [93, 94]. In lung biopsy specimens form
patients with COPD, Western blot detected elevated
level of LC3b-II protein when compared with non-COPD
control patients. e level of LC3b-II correlated posi-
tively with clinical severity as measured by global ini-
tiative for COPD score [95]. Further studies confirmed
that exposure of lung epithelial cell lines and fibroblasts
to cigarette smoke extract induced the accumulation of
autophagosomes on electron micrographs and enhanced
levels of LC3b-II protein [96]; while genetic depletion of
two macroautophagy pathway members, Beclin-1 and
LC3b, reduced the rate of cell death in cigarette smoke
extract-exposed cells [97]. Besides, studies also found that
the macroautophagic flux in macrophages from COPD
patients was greatly inhibited, which may contribute to
the excessive inflammatory response in airway [98].
Other systemic inammatory diseases
Genome-wide association studies have linked several sin-
gle nucleotide polymorphisms in Atg5 to systemic lupus
erythematosus susceptibility [99]. Systemic lupus erythe-
matosus is a multifactorial, heterogeneous disease char-
acterized by autoimmune responses against self-antigens
generated from dying cells. However, further studies are
needed to determine the link between autophagy and
systemic lupus erythematosus pathogenesis. Studies also
suggested that defects in autophagy might contribute to
inflammation-associated metabolic diseases such as dia-
betes and obesity via effecting on endoplasmic reticulum
stress and insulin resistance [100].
Therapeutic potential andfuture perspective
e present review summarized the previous studies
which discussed the role of autophagic processes in the
pathogenesis of inflammation, including elimination
of pathogens, regulation of innate or adaptive immune
response. Besides, we also referred to the potential thera-
peutic role of autophagy in some inflammatory diseases.
Recently, increasing evidences also identified its role in
carcinogenesis [101]. ese observations collectively
implicate that autophagy is an important modulator of
disease pathogenesis. However, although progress has
been made in elucidation the role of macroautophagy in
inflammation, our understanding of the molecular mech-
anisms and pathways of autophagy and its relationship
with inflammatory of inflammatory disease is still quite
As with any other core cellular processes, turning
basic science knowledge about autophagy into thera-
pies is difficult because of the interdependent nature
of biochemical pathways. However, from a clinical per-
spective, the contributions of macroautophagy to the
pathogenesis of inflammation and inflammatory dis-
eases have potential therapeutic and diagnostic impli-
cations. From a therapeutic standpoint, the possibility
that macroautophagy may play different physiological
roles is depending on the cell type; as well as the fact that
its different functions in different inflammatory condi-
tions will lead to the result that when simply providing
a chemical stimulator or inhibitor of macroautophagy to
patients, they could have unpredictable consequences,
such as improving symptoms or getting worse. From a
diagnostic standpoint, the fact that macroautophagy
marker proteins such as LC3b are increased before the
onset of apoptosis suggests that they might prove use-
ful as early biomarkers of some inflammatory disease.
Future research will focus on the detailed mechanisms
of autophagy pathways in specific diseases, as well as the
interaction of autophagy with other pathophysiologi-
cal processes thus determining whether the autophagic
pathway can be manipulated for therapeutic gain in the
treatment of inflammatory diseases and/or other dis-
eases including cancer.
MHC: major histocompatibility complex; ATG: autophagy-related genes; ULK:
unc-51-like kinase; LC3: microtubule-associated protein light chain 3; PI3 K:
phosphatidylinositol 3-kinase; GFP: green fluorescent protein; RFP: red fluores-
cent protein; TLR: toll-like receptor; IL: interleukin; ROS: reactive oxygen spe-
cies; TCR: T cell receptor; IFN: interferon; LPS: lipopolysaccoride; VSV: vesicular
stomatitis virus; CD: Crohn’s disease; PAH: pulmonary arterial hypertension; CF:
cystic fibrosis; CFTR: transmembrane conductance regulator; COPD: chronic
obstructive pulmonary disease.
Authors’ contributions
MJQ and XCF was involved in the conception, design and drafting of the
manuscript. XDW was involved in the revision and final acceptance of the
manuscript. All authors read and approved the final manuscript.
The work was supported by Shanghai Leading Academic Discipline Project
(B115), Zhongshan Distinguished Professor Grant (XDW), The National Nature
Science Foundation of China (91230204, 81270099, 81320108001, 81270131,
81400035, 81570075, 81500058, 81500025), The Shanghai Committee of Sci-
ence and Technology (12JC1402200, 12431900207, 11410708600).
Competing interests
The authors declare that they have no competing interests.
The work was supported by Shanghai Leading Academic Discipline Project
(B115), Zhongshan Distinguished Professor Grant (XDW), The National Nature
Science Foundation of China (91230204, 81270099, 81320108001, 81270131,
81400035, 81570075, 81500058, 81500025), The Shanghai Committee of Sci-
ence and Technology (12JC1402200, 12431900207, 11410708600).
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 21 March 2017 Accepted: 18 July 2017
Page 9 of 11
Qian et al. Clin Trans Med (2017) 6:24
1. Wang C, Wang Y, McNutt MA, Zhu WG (2011) Autophagy process is
associated with anti-neoplastic function. Acta Biochim Biophys Sin
2. Fougeray S, Pallet N (2015) Mechanisms and biological functions of
autophagy in diseased and ageing kidneys. Nat Rev Nephrol 11:34–45
3. Chaabane W, User SD, El-Gazzah M, Jaksik R, Sajjadi E, Rzeszowska-
Wolny J et al (2013) Autophagy, apoptosis, mitoptosis and necrosis:
interdependence between those pathways and effects on cancer. Arch
Immunol Ther Exp 61:43–58
4. Keta O, Bulat T, Golić I et al (2016) The impact of autophagy on cell
death modalities in CRL-5876 lung adenocarcinoma cells after their
exposure to γ-rays and/or erlotinib. Cell Biol Toxicol 32(2):83–101.
5. Zhong Z, Sanchez-Lopez E, Karin M (2016) Autophagy, inflamma-
tion, and Immunity: a troika governing cancer and its treatment. Cell
6. Saitoh T, Akira S (2010) Regulation of innate immune responses by
autophagy-related proteins. J Cell Biol 189:925–935
7. Pan H, Chen L, Xu Y, Han W, Lou F, Fei W et al (2016) Autophagy-
associated immune responses and cancer immunotherapy. Oncotarget
8. Lee JA, Yue Z, Gao FB (2016) Autophagy in neurodegenerative diseases.
Brain Res 1649:141–142
9. Lai CH, Tsai CC, Kuo WW, Ho TJ, Day CH, Pai PY et al (2016) Multi-strain
probiotics inhibit cardiac myopathies and autophagy to prevent heart
injury in high-fat diet-fed rats. Int J Med Sci 13:277–285
10. Tsukada M, Ohsumi Y (1993) Isolation and characterization of
autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett
11. Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M
et al (1994) Isolation of autophagocytosis mutants of Saccharomyces
cerevisiae. FEBS Lett 349:275–280
12. Xie Z, Klionsky DJ (2007) Autophagosome formation: core machinery
and adaptations. Nat Cell Biol 9:1102–1109
13. Demishtein A, Porat Z, Elazar Z, Shvets E (2015) Applications of flow
cytometry for measurement of autophagy. Methods 75:87–95
14. Guimaraes RS, Delorme-Axford E, Klionsky DJ, Reggiori F (2015) Assays
for the biochemical and ultrastructural measurement of selective and
nonselective types of autophagy in the yeast Saccharomyces cerevisiae.
Methods 75:141–150
15. Kovacs AL (2015) The application of traditional transmission electron
microscopy for autophagy research in Caenorhabditis elegans. Biophys
Rep 1:99–105
16. Liu H, Zhang L, Zhang X, Cui Z (2017) PI3K/AKT/mTOR pathway pro-
motes progestin resistance in endometrial cancer cells by inhibition of
autophagy. Onco Targets Ther 10:2865–2871
17. Lin CW, Jan MS, Kuo JH (2014) Autophagy-related gene expression
analysis of wild-type and atg5 gene knockout mouse embryonic fibro-
blast cells treated with polyethylenimine. Mol Pharm 11:3002–3008
18. Dong RQ, Wang ZF, Zhao C, Gu HR, Hu ZW, Xie J et al (2015) Toll-like
receptor 4 knockout protects against isoproterenol-induced cardiac
fibrosis: the role of autophagy. J Cardiovasc Pharmacol Ther 20:84–92
19. Hosok awa N, Hara Y, Mizushima N (2007) Generation of cell lines with
tetracycline-regulated autophagy and a role for autophagy in control-
ling cell size. FEBS Lett 581:2623–2629
20. Satoh T, Akira S (2012) Physiological roles and differentiation mecha-
nism of M2 macrophage. Nihon Rinsho Jpn J Clin Med 70(Suppl
21. Franco LH, Fleuri AKA, Pellison NAC, Quirino GFS, Horta CV, Carvalho
RVH et al (2017) Autophagy downstream of endosomal toll-like recep-
tors signaling in macrophages is a key mechanism for resistance to
leishmania major infection. J Biol Chem. doi:10.1074/jbc.M117.780981
22. Agrawal V, Jaiswal MK, Mallers T, Katara GK, Gilman-Sachs A, Beaman KD
et al (2015) Altered autophagic flux enhances inflammatory responses
during inflammation-induced preterm labor. Sci Rep 5:9410
23. Zhao Z, Fux B, Goodwin M, Dunay IR, Strong D, Miller BC et al (2008)
Autophagosome-independent essential function for the autophagy
protein Atg5 in cellular immunity to intracellular pathogens. Cell Host
Microbe 4:458–469
24. Lai YC, Chuang YC, Chang CP, Yeh TM (2015) Macrophage migration
inhibitory factor has a permissive role in concanavalin A-induced cell
death of human hepatoma cells through autophagy. Cell Death Dis
25. Thieblemont N, Wright HL, Edwards SW, Witko-Sarsat V (2016) Human
neutrophils in auto-immunity. Semin Immunol 28:159–173
26. Witter AR, Okunnu BM, Berg RE (2016) The essential role of neutrophils
during infection with the intracellular bacterial pathogen Listeria mono-
cytogenes. J Immunol 197:1557–1565
27. Herrmann JM, Meyle J (2000) Neutrophil activation and periodontal
tissue injury. Periodontology 2015(69):111–127
28. El Kebir D, Filep JG (2013) Targeting neutrophil apoptosis for enhancing
the resolution of inflammation. Cells 2:330–348
29. Suzuki E, Maverakis E, Sarin R, Bouchareychas L, Kuchroo VK, Nestle FO
et al (2016) T cell-independent mechanisms associated with neutrophil
extracellular trap formation and selective autophagy in IL-17A-medi-
ated epidermal hyperplasia. J Immunol 197:4403–4412
30. Itoh H, Matsuo H, Kitamura N, Yamamoto S, Higuchi T, Takematsu H et al
(2015) Enhancement of neutrophil autophagy by an IVIG preparation
against multidrug-resistant bacteria as well as drug-sensitive strains. J
Leukoc Biol 98:107–117
31. Mihalache CC, Yousefi S, Conus S, Villiger PM, Schneider EM, Simon
HU (2011) Inflammation-associated autophagy-related programmed
necrotic death of human neutrophils characterized by organelle fusion
events. J Immunol 186:6532–6542
32. Tang S, Zhang Y, Yin SW, Gao XJ, Shi WW, Wang Y et al (2015) Neutrophil
extracellular trap formation is associated with autophagy-related
signalling in ANCA-associated vasculitis. Clin Exp Immunol 180:408–418
33. Zhou J, Zhu Z, Bai C, Sun H, Wang X (2014) Proteomic profiling of
lymphocytes in autoimmunity, inflammation and cancer. J Transl Med
34. Wang DC, Wang X, Chen C (2016) Effects of anti-human T lymphocyte
immune globulins in patients: new or old. J Cell Mol Med 20:1796–1799
35. Riffelmacher T, Simon AK (2017) Mechanistic roles of autophagy in
hematopoietic differentiation. FEBS J 284:1008–1020
36. Schuster C, Gerold KD, Schober K, Probst L, Boerner K, Kim MJ et al
(2015) The autoimmunity-associated gene CLEC16A modulates
thymic epithelial cell autophagy and alters T cell selection. Immunity
37. Stephenson LM, Miller BC, Ng A, Eisenberg J, Zhao Z, Cadwell K et al
(2009) Identification of Atg5-dependent transcriptional changes and
increases in mitochondrial mass in Atg5-deficient T lymphocytes.
Autophagy 5:625–635
38. Honda S, Arak awa S, Nishida Y, Yamaguchi H, Ishii E, Shimizu S (2014)
Ulk1-mediated Atg5-independent macroautophagy mediates elimina-
tion of mitochondria from embryonic reticulocytes. Nat Commun
39. K abat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF,
Laing A et al (2016) The autophagy gene Atg16l1 differentially regulates
Treg and TH2 cells to control intestinal inflammation. ELife 5:e12444
40. van Loosdregt J, Rossetti M, Spreafico R, Moshref M, Olmer M, Williams
GW et al (2016) Increased autophagy in CD4+ T cells of rheumatoid
arthritis patients results in T-cell hyperactivation and apoptosis resist-
ance. Eur J Immunol 46:2862–2870
41. Munz C (2016) Autophagy proteins in antigen processing for presenta-
tion on MHC molecules. Immunol Rev 272:17–27
42. Munz C (2016) Autophagy beyond intracellular MHC class II antigen
presentation. Trends Immunol 37:755–763
43. Chemali M, Radtke K, Desjardins M, English L (2011) Alternative path-
ways for MHC class I presentation: a new function for autophagy. Cell
Mol Life Sci 68:1533–1541
44. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK et al
(2008) The autophagy gene ATG5 plays an essential role in B lympho-
cyte development. Autophagy 4:309–314
45. Arsov I, Adebayo A, Kucerova-Levisohn M, Haye J, MacNeil M, Papa-
vasiliou FN et al (2011) A role for autophagic protein beclin 1 early in
lymphocyte development. J Immunol 186:2201–2209
46. Zhou A, Li S, Khan FA, Zhang S (2016) Autophagy postpones apoptotic
cell death in PRRSV infection through Bad-Beclin1 interaction. Virulence
Page 10 of 11
Qian et al. Clin Trans Med (2017) 6:24
47. Hosogi S, Kusuzaki K, Inui T, Wang X, Marunaka Y (2014) Cytosolic
chloride ion is a key factor in lysosomal acidification and function of
autophagy in human gastric cancer cell. J Cell Mol Med 18:1124–1133
48. Wu TT, Li WM, Yao YM (2016) Interactions between autophagy and
inhibitory cytokines. Int J Biol Sci 12:884–897
49. Shi L, Dong N, Fang X, Wang X (2016) Regulatory mechanisms of TGF-
beta1-induced fibrogenesis of human alveolar epithelial cells. J Cell Mol
Med 20:2183–2193
50. Sandri M (2010) Autophagy in health and disease. 3. Involve-
ment of autophagy in muscle atrophy. Am J Physiol Cell Physiol
51. Chen D, Liu J, Lu L, Huang Y, Wang Y, Wang M et al (2016) Emodin
attenuates TNF-alpha-induced apoptosis and autophagy in mouse
C2C12 myoblasts though the phosphorylation of Akt. Int Immunophar-
macol 34:107–113
52. Wang XH, Zhu L, Hong X, Wang YT, Wang F, Bao JP et al (2016) Res-
veratrol attenuated TNF-alpha-induced MMP-3 expression in human
nucleus pulposus cells by activating autophagy via AMPK/SIRT1 signal-
ing pathway. Exp Biol Med (Maywood) 241:848–853
53. Jia G, Cheng G, Gangahar DM, Agrawal DK (2006) Insulin-like growth
factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal
kinase and Akt pathways in human atherosclerotic vascular smooth
cells. Immunol Cell Biol 84:448–454
54. Sivaprasad U, Basu A (2008) Inhibition of ERK attenuates autophagy and
potentiates tumour necrosis factor-alpha-induced cell death in MCF-7
cells. J Cell Mol Med 12:1265–1271
55. Venkatesan T, Choi YW, Mun SP, Kim YK (2016) Pinus radiata bark extract
induces caspase-independent apoptosis-like cell death in MCF-7
human breast cancer cells. Cell Biol Toxicol 32:451–464
56. Shen X, Ma L, Dong W, Wu Q, Gao Y, Luo C et al (2016) Autophagy regu-
lates intracerebral hemorrhage induced neural damage via apoptosis
and NF-kappaB pathway. Neurochem Int 96:100–112
57. Park HJ, Lee SJ, Kim SH, Han J, Bae J, Kim SJ et al (2011) IL-10 inhibits the
starvation induced autophagy in macrophages via class I phosphati-
dylinositol 3-kinase (PI3K) pathway. Mol Immunol 48:720–727
58. Ni Cheallaigh C, Keane J, Lavelle EC, Hope JC, Harris J (2011) Autophagy
in the immune response to tuberculosis: clinical perspectives. Clin Exp
Immunol 164:291–300
59. Ding Y, Choi ME (2014) Regulation of autophagy by TGF-beta: emerging
role in kidney fibrosis. Semin Nephrol 34:62–71
60. Xue H, Yuan G, Guo X, Liu Q, Zhang J, Gao X et al (2016) A novel
tumor-promoting mechanism of IL6 and the therapeutic efficacy of
tocilizumab: hypoxia-induced IL6 is a potent autophagy initiator in
glioblastoma via the p-STAT3-MIR155-3p-CREBRF pathway. Autophagy
61. Khan NM, Ansari MY, Haqqi TM (2017) Sucrose, but not glucose, blocks
IL1-beta-induced inflammatory response in human chondrocytes by
inducing autophagy via AKT/mTOR pathway. J Cell Biochem 118:629–639
62. Liu ZQ, Zhao S, Fu WQ (2016) Insulin-like growth factor 1 antagonizes
lumbar disc degeneration through enhanced autophagy. Am J Transl
Res 8:4346–4353
63. Wang X, Qi H, Wang Q, Zhu Y, Jin M, Tan Q et al (2015) FGFR3/fibroblast
growth factor receptor 3 inhibits autophagy through decreasing the
ATG12-ATG5 conjugate, leading to the delay of cartilage development
in achondroplasia. Autophagy 11:1998–2013
64. Crisan TO, Plantinga TS, van de Veerdonk FL, Farcas MF, Stoffels M,
Kullberg BJ et al (2011) Inflammasome-independent modulation of
cytokine response by autophagy in human cells. PLoS ONE 6:e18666
65. Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, Oliver-De La
Cruz J, Guerri C (2014) Role of mitochondria ROS generation in ethanol-
induced NLRP3 inflammasome activation and cell death in astroglial
cells. Front Cell Neurosci 8:216
66. Wang Q, Ren J (2016) mTOR-independent autophagy inducer trehalose
rescues against insulin resistance-induced myocardial contractile
anomalies: role of p38 MAPK and Foxo1. Pharmacol Res 111:357–373
67. Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA et al (2011)
Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for
degradation. J Biol Chem 286:9587–9597
68. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007)
Autophagy-dependent viral recognition by plasmacytoid dendritic
cells. Science 315:1398–1401
69. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ
et al (2007) The Atg5 Atg12 conjugate associates with innate antiviral
immune responses. Proc Natl Acad Sci USA 104:14050–14055
70. Shrivastava S, Raychoudhuri A, Steele R, Ray R, Ray RB (2011) Knock-
down of autophagy enhances the innate immune response in hepatitis
C virus-infected hepatocytes. Hepatology 53:406–414
71. Medvedev R, Hildt E, Ploen D (2017) Look who’s talking-the crosstalk
between oxidative stress and autophagy supports exosomal-depend-
ent release of HCV particles. Cell Biol Toxicol 33(3):211–231
72. Rubin DT, Feld LD, Goeppinger SR, Margolese J, Rosh J, Rubin M et al
(2017) The Crohn’s and colitis foundation of america survey of inflam-
matory bowel disease patient health care access. Inflamm Bowel Dis
73. K aarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J (2017) Autophagy
regulates death of retinal pigment epithelium cells in age-related
macular degeneration. Cell Biol Toxicol 33(2):113–128
74. Quaglietta L, te Velde A, Staiano A, Troncone R, Hommes DW (2007)
Functional consequences of NOD2/CARD15 mutations in Crohn
disease. J Pediatr Gastroenterol Nutr 44:529–539
75. Boada-Romero E, Serramito-Gomez I, Sacr istan MP, Boone DL, Xavier RJ,
Pimentel-Muinos FX (2016) The T300A Crohn’s disease risk polymorphism
impairs function of the WD40 domain of ATG16L1. Nat Commun 7:11821
76. Rufini S, Ciccacci C, Di Fusco D, Ruffa A, Pallone F, Novelli G et al (2015)
Autophagy and inflammatory bowel disease: association between vari-
ants of the autophagy-related IRGM gene and susceptibility to Crohn’s
disease. Dig Liver Dis 47:744–750
77. Lippai M, Szatmari Z (2017) Autophagy-from molecular mechanisms to
clinical relevance. Cell Biol Toxicol 33(2):145–168
78. Yu X, Li C, Hong W, Pan W, Xie J (2013) Autophagy during Mycobac-
terium tuberculosis infection and implications for future tuberculosis
medications. Cell Signal 25:1272–1278
79. Deretic V, Delgado M, Vergne I, Master S, De Haro S, Ponpuak M et al
(2009) Autophagy in immunity against Mycobacterium tuberculosis: a
model system to dissect immunological roles of autophagy. Curr Top
Microbiol Immunol 335:169–188
80. Honda A, Harrington E, Cornella-Taracido I, Furet P, Knapp MS, Glick M
et al (2016) Potent, selective, and orally bioavailable inhibitors of VPS34
provide chemical tools to modulate autophagy in vivo. ACS Med Chem
Lett 7:72–76
81. Rolando M, Escoll P, Buchrieser C (2016) Legionella pneumophila
restrains autophagy by modulating the host’s sphingolipid metabolism.
Autophagy 12:1053–1054
82. Lohia R, Jain P, Jain M, Burma PK, Shrivastava A, Saran S (2017) Dictyos-
telium discoideum Sir2D protein, an ortholog of human 1 SIRT1, modu-
lates cell type specific gene expression and is involved in autophagy.
Int J Dev Biol 61(1–2):95–104. doi:10.1387/ijdb.160038ss
83. Krokowski S, Lobato-Marquez D, Mostowy S (2016) Mitochondria
promote septin assembly into cages that entrap Shigella for autophagy.
Autophagy. doi:10.1080/15548627.2016.1228496
84. Skride A, Sablinskis K, Avidan Y, Rudzitis A, Lejnieks A (2017) Pulmonary
arterial hypertension associated with connective tissue disease: insights
from latvian PAH registry. Eur J Intern Med 40:e13–e14
85. Lee SJ, Smith A, Guo L, Alastalo TP, Li M, Sawada H et al (2011)
Autophagic protein LC3B confers resistance against hypoxia-induced
pulmonary hypertension. Am J Respir Crit Care Med 183:649–658
86. Lahm T, Petrache I (2012) LC3 as a potential therapeutic target in
hypoxia-induced pulmonary hypertension. Autophagy 8:1146–1147
87. Zhou Y, Zhang S, Dai C, Tang S, Yang X, Li D et al (2016) Quinocetone
triggered ER stress-induced autophagy via ATF6/DAPK1-modulated
mAtg9a trafficking. Cell Biol Toxicol 32:141–152
88. Leung GK, Ying D, Mak CC, Chen XY, Xu W, Yeung KS et al (2017) CFTR
founder mutation causes protein trafficking defects in Chinese patients
with cystic fibrosis. Mol Genet Genom Med 5:40–49
89. Velentzas PD, Velentzas AD, Mpakou VE, Antonelou MH, Margaritis LH,
Papassideri IS, Stravopodis DJ (2013) Detrimental effects of proteasome
inhibition activity in Drosophila melanogaster: implication of ER stress,
autophagy, and apoptosis. Cell Biol Toxicol 29(1):13–37
90. Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, Settembre
C et al (2010) Defective CFTR induces aggresome formation and lung
inflammation in cystic fibrosis through ROS-mediated autophagy
inhibition. Nat Cell Biol 12:863–875
Page 11 of 11
Qian et al. Clin Trans Med (2017) 6:24
91. Wu X, Sun X, Chen C, Bai C, Wang X (2014) Dynamic gene expressions
of peripheral blood mononuclear cells in patients with acute exacerba-
tion of chronic obstructive pulmonary disease: a preliminary study. Crit
Care 18:508
92. Wang X (2016) New biomarkers and therapeutics can be discovered
during COPD-lung cancer transition. Cell Biol Toxicol 32:359–361
93. Zhang X, Yin H, Li Z, Zhang T, Yang Z (2016) Nano-TiO2 induces
autophagy to protect against cell death through antioxidative mecha-
nism in podocytes. Cell Biol Toxicol 32(6):513–527
94. Wu X, Yuan B, Lopez E, Bai C, Wang X (2014) Gene polymorphisms and
chronic obstructive pulmonary disease. J Cell Mol Med 18:15–26
95. Denardin CC, Martins LA, Parisi MM et al (2017) Autophagy induced
by purple pitanga (Eugenia uniflora L.) extract triggered a coopera-
tive effect on inducing the hepatic stellate cell death. Cell Biol Toxicol
96. Chen ZH, Lam HC, Jin Y, Kim HP, Cao J, Lee SJ et al (2010) Autophagy
protein microtubule-associated protein 1 light chain-3B (LC3B) acti-
vates extrinsic apoptosis during cigarette smoke-induced emphysema.
Proc Natl Acad Sci USA 107:18880–18885
97. Alarcon-Riquelme ME, Ziegler JT, Molineros J, Howard TD, Moreno-
Estrada A, Sanchez-Rodriguez E et al (2016) Genome-wide association
study in an amerindian ancestry population reveals novel systemic
lupus erythematosus risk loci and the role of European admixture.
Arthritis Rheumatol 68:932–943
98. Vij N, Chandramani P, Westphal CV, Hole R, Bodas M (2016) Cigarette
smoke induced autophagy-impairment accelerates lung aging, COPD-
emphysema exacerbations and pathogenesis. Am J Physiol Cell Physiol.
99. You Y, Zhai ZF, Chen FR, Chen W, Hao F (2015) Autoimmune risk loci
of IL12RB2, IKZF1, XKR6, TMEM39A and CSK in Chinese patients with
systemic lupus erythematosus. Tissue Antigens 85:200–203
100. Soussi H, Clement K, Dugail I (2016) Adipose tissue autophagy status
in obesity: expression and flux–two faces of the picture. Autophagy
101. Carchman EH, Matkowskyj KA, Meske L, Lambert PF (2016) Dysregu-
lation of autophagy contributes to anal carcinogenesis. PLoS ONE
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Cancer formation is a highly regulated and complex process, largely dependent on its microenvironment. This complexity highlights the need for developing novel target-based therapies depending on cancer phenotype and genotype. Autophagy, a catabolic process, removes damaged and defective cellular materials through lysosomes. It is activated in response to stress conditions such as nutrient deprivation, hypoxia, and oxidative stress. Oxidative stress is induced by excess reactive oxygen species (ROS) that are multifaceted molecules that drive several pathophysiological conditions, including cancer. Moreover, autophagy also plays a dual role, initially inhibiting tumor formation but promoting tumor progression during advanced stages. Mounting evidence has suggested an intricate crosstalk between autophagy and ROS where they can either suppress cancer formation or promote disease etiology. This review highlights the regulatory roles of autophagy and ROS from tumor induction to metastasis. We also discuss the therapeutic strategies that have been devised so far to combat cancer. Based on the review, we finally present some gap areas that could be targeted and may provide a basis for cancer suppression.
... As with Grn-lacking mice models, MS patients display similar mRNA and protein profiles of ATG7 and LC3-II ( Figure 2 and Table 3) . These findings of autophagy impairment are associated with an inflammatory response, which modulate autophagy by generating immune cells (e.g., neutrophils, macrophages, and lymphocytes), as well as inducing transcriptional changes in cytokine production (Li et al., 2014;Qian et al., 2017). HaCaT cells are human keratinocytes under inflammatory conditions that demonstrate high endogenous levels of GRN (Tian et al., 2016). ...
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The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a family of neurodegenerative diseases that affect all age groups and ethnicities around the globe. At least a dozen NCL subtypes have been identified that are each linked to a mutation in a distinct ceroid lipofuscinosis neuronal (CLN) gene. Mutations in CLN genes cause the accumulation of autofluorescent lipoprotein aggregates, called ceroid lipofuscin, in neurons and other cell types outside the central nervous system. The mechanisms regulating the accumulation of this material are not entirely known. The CLN genes encode cytosolic, lysosomal, and integral membrane proteins that are associated with a variety of cellular processes, and accumulated evidence suggests they participate in shared or convergent biological pathways. Research across a variety of non-mammalian and mammalian model systems clearly supports an effect of CLN gene mutations on autophagy, suggesting that autophagy plays an essential role in the development and progression of the NCLs. In this review, we summarize research linking the autophagy pathway to the NCLs to guide future work that further elucidates the contribution of altered autophagy to NCL pathology.
The relationship between autophagy and immunity has been well studied. However, little is known about the role of autophagy in the immune microenvironment during the progression of dilated cardiomyopathy (DCM). Therefore, this study aims to uncover the effect of autophagy on the immune microenvironment in the context of DCM. By investigating the autophagy gene expression differences between healthy donors and DCM samples, 23 dysregulated autophagy genes were identified. Using a series of bioinformatics methods, 13 DCM‐related autophagy genes were screened and used to construct a risk prediction model, which can well distinguish DCM and healthy samples. Then, the connections between autophagy and immune responses including infiltrated immunocytes, immune reaction gene‐sets and human leukocyte antigen (HLA) genes were systematically evaluated. In addition, two autophagy‐mediated expression patterns in DCM were determined via the unsupervised consensus clustering analysis, and the immune characteristics of different patterns were revealed. In conclusion, our study revealed the strong effect of autophagy on the DCM immune microenvironment and provided new insights to understand the pathogenesis and treatment of DCM.
Autophagy is a self-degradation process in cells, which is of vital significance to the health and operation of organisms. Due to the increase of lysosomal viscosity during autophagy, viscosity probes that specifically accumulate in lysosome are powerful tools for monitoring autophagy and investigating related diseases. However, there is still a lack of viscosity-sensitive ratiometric autophagy probes, which restricts the tracking of autophagy with high accuracy in complex physiological environment. Herein, a viscosity-responsive, lysosome targeted two-photon fluorescent probe Lyso-Vis was designed based on through bond energy transfer (TBET) mechanism. The TBET-based probe achieved the separation of two emission baselines, which greatly improved the resolution and reliability of sensing and imaging. Under 810 nm two-photon excitation, the emission intensity ratio of the red and green channel increased with a viscosity dependent manner. Lyso-Vis not only for the first time realized ratiometric sensing of lysosomal viscosity during autophagy process, but also visualized the association of autophagy with inflammation and stroke, and it was applied to explore the activation and inhibition of autophagy during stroke in mice.
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Autophagy is a highly conserved metabolic process with a cytoprotective function. Autophagy is involved in cancer, infection, immunity, and inflammation and may be a potential therapeutic target. Increasing evidence has revealed that autophagy has primary implications for esophageal cancer, including its initiation, progression, tumor microenvironment (TME) modification, diagnosis, and treatment. Notably, autophagy displayed excellent application potential in radiotherapy combined with immunotherapy. Radiotherapy combined with immunotherapy is a new potential therapeutic strategy for cancers, including esophageal cancer. Autophagy modulators can work as adjuvant enhancers in radiotherapy or immunotherapy of cancers. This review highlights the most recent data related to the role of autophagy regulation in esophageal cancer.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its highly reactive inflammatory desmoplastic stroma with evidence of an extensive tumor stromal interaction largely mediated by inflammatory factors. KRAS mutation and inflammatory signaling promote protumorigenic events, including metabolic reprogramming with several inter-regulatory crosstalks to fulfill the high demand of energy and regulate oxidative stress for tumor growth and progression. Notably, the more aggressive molecular subtype of PDAC enhances influx of glycolytic intermediates. This review focuses on the interactive role of inflammatory signaling and metabolic reprogramming with emerging evidence of crosstalk, which supports the development, progression, and therapeutic resistance of PDAC. Understanding the emerging crosstalk between inflammation and metabolic adaptations may identify potential targets and develop novel therapeutic approaches for PDAC.
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Obesity is a feature of metabolic syndrome with chronic inflammation in obese subjects, characterized by adipose tissue (AT) expansion, proinflammatory factor overexpression, and macrophage infiltration. Autophagy modulates inflammation in the enlargement of AT as an essential step for maintaining the balance in energy metabolism and waste elimination. Signaling originating from dysfunctional AT, such as AT containing hypertrophic adipocytes and surrounding macrophages, activates NOD-like receptor family 3 (NLRP3) inflammasome. There are interactions about altered autophagy and NLRP3 inflammasome activation during the progress in obesity. We summarize the current studies and potential mechanisms associated with autophagy and NLRP3 inflammasome in AT inflammation and aim to provide further evidence for research on obesity and obesity-related complications.
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Leishmaniasis is caused by protozoan parasites of the genus Leishmania. In mammalians, these parasites survive and replicate in macrophages and parasite elimination by macrophages is critical for host resistance. Endosomal Toll-like receptors (TLRs) have been shown to be crucial for resistance to L. major in vivo. For example, mice in the resistant C57BL/6 genetic background that are triple-deficient for TLR3, -7 and -9 (Tlr3/7/9-/-) are highly susceptible to L. major infection. Tlr3/7/9-/- mice are as susceptible as mice deficient in MyD88 or UNC93B1, a chaperone required for appropriate localization of endosomal TLRs, but the mechanisms are unknown. Here we found that macrophages infected with L. major undergo autophagy, which effectively accounted for restriction of parasite replication. Signaling via endosomal TLRs was required for autophagy because macrophages deficient for TLR3, -7 and 9, UNC93B1 or MyD88 failed to undergo L. major-induced autophagy. We also confirmed that Myd88-/-, Tlr3/7/9-/-, and Unc93b1-/- cells were highly permissive to L. major replication. Accordingly, shRNA-mediated suppression of Atg5, an E3 ubiquitin ligase essential for autophagosome elongation, in macrophages impaired the restriction of L. major replication in C57BL/6, but did not affect parasite replication in Myd88-/- or Unc93b1-/- macrophages. Rapamycin treatment reduced inflammatory lesions formed in the ears of Leishmania-infected C57BL/6 and Tlr3/7/9-/- mice, indicating that autophagy operates downstream of TLR signaling and is relevant for disease development in vivo. Collectively, our results indicate that autophagy contributes to macrophage resistance to L. major replication, and mechanistically explain the previously described endosomal TLR mediated resistance to L. major infection.
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Hua Liu,1,2 Liqin Zhang,2 Xuyan Zhang,2 Zhumei Cui1 1Department of Gynecology, Affiliated Hospital of Qingdao Medical College, Qingdao University, Qingdao, 2Department of Gynecology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China Abstract: Endometrial cancer (EC) is now one of the most common malignant tumors in young women. In all, 90% of young patients with EC have a high expression of progesterone recep­tor, can be treated with progestin, and have very good prognosis. However, some of the young EC patients are resistant to progestin, the mechanism of which is unclear. To illuminate the mechanism by which endometrial cells acquire progestin resistance, we treated Ishikawa cells by slowly increasing dosage of progestin and established a progestin-resistant cell subline. We show here that progesterone resistant cells acquire increased proliferation rate and interestingly decreased autophagy. To uncover the mechanism by which cells increase proliferation and bypass autophagy, we found higher activation of phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway was necessary to this malignant acquirement by RNAi technique. Further, we elucidated that activation of mTOR was sufficient and necessary for progestin resistance. RAD001, an inhibitor of mTOR, decreased phosphorylation of mTOR and inhibited proliferation of progestin-resistant cancer cells by promoting autophagy. Thus, our results indicated that mTOR can be a target to treat the progestin-resistant EC. Keywords: progesterone receptor, RAD001, proliferation, Ishikawa, phosphorylation
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Autophagy is a highly conserved and regulated intracellular lysosomal degradation pathway that is essential for cell survival. Dysregulation has been linked to the development of various human diseases, including neurodegeneration and tumorigenesis, infection, and aging. Besides, many viruses hijack the autophagosomal pathway to support their life cycle. The hepatitis C virus (HCV), a major cause of chronic liver diseases worldwide, has been described to induce autophagy. The autophagosomal pathway can be further activated in response to elevated levels of reactive oxygen species (ROS). HCV impairs the Nrf2/ARE-dependent induction of ROS-detoxifying enzymes by a so far unprecedented mechanism. In line with this, this review aims to discuss the relevance of HCV-dependent elevated ROS levels for the induction of autophagy as a result of the impaired Nrf2 signaling and the described crosstalk between p62 and the Nrf2/Keap1 signaling pathway. Moreover, autophagy is functionally connected to the endocytic pathway as components of the endosomal trafficking are involved in the maturation of autophagosomes. The release of HCV particles is still not fully understood. Recent studies suggest an involvement of exosomes that originate from the endosomal pathway in viral release. In line with this, it is tempting to speculate whether HCV-dependent elevated ROS levels induce autophagy to support exosome-mediated release of viral particles. Based on recent findings, in this review, we will further highlight the impact of HCV-induced autophagy and its interplay with the endosomal pathway as a novel mechanism for the release of HCV particles.
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Autophagy is a lysosomal degradation pathway of eukaryotic cells that is highly conserved from yeast to mammals. During this process, cooperating protein complexes are recruited in a hierarchic order to the phagophore assembly site (PAS) to mediate the elongation and closure of double-membrane vesicles called autophagosomes, which sequester cytosolic components and deliver their content to the endolysosomal system for degradation. As a major cytoprotective mechanism, autophagy plays a key role in the stress response against nutrient starvation, hypoxia, and infections. Although numerous studies reported that impaired function of core autophagy proteins also contributes to the development and progression of various human diseases such as neurodegenerative disorders, cardiovascular and muscle diseases, infections, and different types of cancer, the function of this process in human diseases remains unclear. Evidence often suggests a controversial role for autophagy in the pathomechanisms of these severe disorders. Here, we provide an overview of the molecular mechanisms of autophagy and summarize the recent advances on its function in human health and disease.
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Age-related macular degeneration (AMD) is an eye disease underlined by the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillares, but the exact mechanism of cell death in AMD is not completely clear. This mechanism is important for prevention of and therapeutic intervention in AMD, which is a hardly curable disease. Present reports suggest that both apoptosis and pyroptosis (cell death dependent on caspase-1) as well as necroptosis (regulated necrosis dependent on the proteins RIPK3 and MLKL, caspase-independent) can be involved in the AMD-related death of RPE cells. Autophagy, a cellular clearing system, plays an important role in AMD pathogenesis, and this role is closely associated with the activation of the NLRP3 inflammasome, a central event for advanced AMD. Autophagy can play a role in apoptosis, pyroptosis, and necroptosis, but its contribution to AMD-specific cell death is not completely clear. Autophagy can be involved in the regulation of proteins important for cellular antioxidative defense, including Nrf2, which can interact with p62/SQSTM, a protein essential for autophagy. As oxidative stress is implicated in AMD pathogenesis, autophagy can contribute to this disease by deregulation of cellular defense against the stress. However, these and other interactions do not explain the mechanisms of RPE cell death in AMD. In this review, we present basic mechanisms of autophagy and its involvement in AMD pathogenesis and try to show a regulatory role of autophagy in RPE cell death. This can result in considering the genes and proteins of autophagy as molecular targets in AMD prevention and therapy.
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Background Cystic fibrosis (CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation. Method Using our in‐house next‐generation sequencing (NGS) pipeline for childhood bronchiectasis, we identified disease‐causing CFTR mutations in CF patients in Hong Kong. After identifying p.I1023R in multiple patients, haplotype analysis was performed with genome‐wide microarray to ascertain the likelihood of this being a founder mutation. We also assessed the processing and gating activity of the mutant protein by Western hybridization and patch‐clamp test. Results Molecular diagnoses were confirmed in four patients, three of whom shared a missense mutation: CFTR:c.3068T>G:p.I1023R. The results suggested that p.I1023R is a founder mutation in southern Han Chinese. In addition, the processing and gating activity of the mutant protein was assessed by gel electrophoresis and a patch‐clamp test. The mutant protein exhibited trafficking defects, suggesting that the dysfunction is caused by reduced cell surface expression of the fully glycosylated proteins. Conclusion Together with other previously reported mutations, the specific founder mutation presented herein suggests a unique CFTR mutation spectrum in the southern Chinese populations, and this finding has vital implications for improving molecular testing and mutation‐specific treatments for Chinese patients with CF.
A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory d
Background: Despite anecdotal information about unaffordable care for patients with inflammatory bowel disease (IBD), there are no data regarding access to health care resources and expert care for patients with IBD. Our study was designed to assess IBD patients' ability to access and use care, as well as the timeliness, affordability, and financial stressors related to care. Methods: We modified the Centers for Disease Control National Health Interview Survey for IBD. The resultant 59-question survey was electronically mailed to the entire Crohn's and Colitis Foundation of America (CCFA) mailing list. Three thousand six hundred eight adult U.S. respondents completed the survey. Statistical analysis was performed. Results: Respondents who had insurance coverage were 96.1%, but 66.3% reported health care-related financial worry. Of the 452 patients who tried to obtain new insurance coverage in the year prior, 60.1% (n = 270) reported difficulty finding sufficient coverage. We found that 25.4% (n = 897) of patients reported delays in medical care, and 48.0% (n = 431) of those respondents reported that the delay was due to cost concerns. Respondents who were denied coverage by an insurance company were 55.3%. Risk factors for emergency department utilization included Crohn's disease, younger age, female sex, lower income, non-White race, and steroid therapy. Conclusions: Our assessment of patient health care access suggests that many patients have health care-related financial worry and have forgone a variety of medical services because of cost, lack of prompt access to care, denial by insurance carriers, and worry over medical coverage. We also identify risk factors for emergency department utilization. These data inform additional studies and interventions to improve access for patients with IBD.
Autophagy has been shown to antagonize the development of Lumbar disc degeneration (LDD), whereas the molecular regulation of autophagy is unknown. We recently reported a potential role of Insulin-like growth factor 1 receptor (IGF1R)/phosphatidylinositol-3 kinase (PI3k)/Akt signaling in the initiation and progression of LDD. Here, we studied the effects of IGF1R signaling on disc cell autophagy. We showed a correction of activation of IGF1R and disc cell autophagy in the resected discs in LDD patients. In vitro, activation of IGF1R signaling antagonized the decreases in cell viability of human disc cells, HNPSV, through suppression of apoptosis and enhancement of autophagy. Suppression of IGF1R signaling or inhibition of autophagy abolished the effects of activation of IGF1R signaling on disc cell survival upon compression. Together, our data suggest that activation of IGF1R may antagonize LDD, at least partially through enhanced autophagy.