Autophagy and inflammation

Abstract

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.

Full text

Qian et al. Clin Trans Med (2017) 6:24
DOI 10.1186/s40169-017-0154-5
REVIEW
Autophagy andinammation
Mengjia Qian, Xiaocong Fang and Xiangdong Wang*
Abstract
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
(http://creativecommons.org/licenses/by/4.0/), 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.
Introduction
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
*Correspondence: xiangdong.wang@clintransmed.org
Zhongshan Hospital Institute of Clinical Science, Shanghai Institute
of Clinical Bioinformatics, Fudan University Medical School, Shanghai,
China

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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.
Measurement
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).
Macrophages
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
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].
Lymphocytes
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
mediators
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

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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,
IL-8

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Autophagy inacute andchronic inammatory
disease
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
primitive.
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.
Abbreviations
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.
Acknowledgements
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.
Funding
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

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Qian et al. Clin Trans Med (2017) 6:24
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