ArticlePDF Available

Autophagy in intestinal injury caused by severe acute pancreatitis

Authors:
Autophagy in intestinal injury caused by severe acute pancreatitis
Hong-Yao Li, Yu-Jie Lin, Ling Zhang, Jing Zhao, Dan-Yang Xiao, Pei-Wu Li
Department of Emergency, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, China.
Severe acute pancreatitis (SAP) is a potentially lethal
disease with considerable morbidity and mortality. It is
often accompanied by systemic inammatory response
syndrome, sepsis, and organ dysfunction.
[1]
It is generally
believed that intestinal barrier dysfunction and bacterial
translocation (BT) are the primary causes of systemic
inammation and sepsis complications in patients with
SAP.
[2]
Recently, increasing evidence has shown that
autophagy plays an important role in intestinal homeosta-
sis. Autophagy can protect the intestinal mucosal barrier
during SAP by degrading and recovering the cytoplasmic
content of intestinal epithelial cells and damaged organelles,
removing invading microorganisms, and participating in
antigen presentation and lymphocyte development.
[2,3]
Therefore, regulating autophagy as a form of treatment
for SAP may bring benecial results.
Autophagy is dened as a catabolic process that is conserved
among all eukaryotic organisms. Its main functions are to
degrade cytoplasmic content and recover damaged organs
andproteinstomaintainintracellular homeostasis when cells
face stress factors such as starvation. Apart from starvation,
autophagy is critical in responding to a diverse range of
stressors namely hypoxia, infection, endoplasmic reticulum
stress, tissue remodeling, cellular debris breakdown, turnover
of damaged organelles, tumor suppression, immune response,
and cell death.
[3,4]
Our current knowledge on autophagy
broadly differentiates it into three types: macroautophagy,
microautophagy, and chaperone-mediated autophagy
(CMA). Among them, CMA is highly specic and has only
been described in mammals so far.
[4,5]
The activation and
execution of autophagy can be divided into two stages: (1)
signal transmission with molecular switches that induce or
turn off autophagy (protein kinase A, mitogen-activated
protein kinase, and mammalian target of rapamycin [mTOR])
and (2) the morphologically detectable execution stage: initial
(dependent on the Unc-51 like autophagy activating kinase 1
complex), nucleation (dependent on BECLIN1-PtdIns3KC3-
ATG14L complex), extension and closure (dependent on
Autophagy protein 12 [Atg12]-Atg5 and light chain 3 [LC3]-
phosphatidylethanolamine conjugate system), and cycling
(dependent on Atg9).
[4,6]
An intact gut mucosa serves as an effective barrier between
the luminal bacterial microbiome as well as stool contents
and the systemic circulation.
[6]
The intestinal mucosal
barrier is mainly divided into biological barriers (intestinal
microorganisms), immune barriers, and mechanical barriers
(intestinal epithelial cells, gap junctions [GJs], and tight
junctions [TJs]).
[3,7]
These barriers maintain host health in
different ways, such as promoting the development and
maturity of the immune system, limiting the direct contact of
microorganisms with the intestinal mucosa, and reducing
the possibility of freeing them from the intestinal lumen. In
addition, adaptive immunity occurs through dendritic cells
(DCs) that continuously sample the bacteria in the lumen to
minimize the exposure of resident bacteria to systemic
immunity and to keep the immunity of the intestinal mucosa
ignorantto the microora.
[3,7]
TJs between cells are gates
or barriers that prevent hydrophilic molecules between
adjacent cells from penetrating to the next cell. GJs channels
provide direct communication between cells and promote
physical adhesion between cells.
[8]
Intestine is one of the remote organs that are damaged in the
SAP process. It is not only a victimof SAP but also further
promotes the deterioration of the disease. Intestinal BT is
considered to be a central mechanism for the development of
AP.
[1]
Microcirculation disorders, uid loss in the third
space, hypovolemia, visceral vasoconstriction, and ische-
mia-reperfusion injury can occur in SAP, which can cause
intestinal reactive oxygen species (ROS). ROS in the
intestine and the storm of inammatory factors are the
main reasons for the damage or obstacles to the mucosal
function of the intestinal mucosal barrier. Impaired
intestinal barrier function allows a large number of
intestinal bacteria and endotoxins to enter the blood and
lymph circulation and nally enter the entire internal
organs, triggering a second attack,and causing secondary
Correspondence to: Dr. Pei-Wu Li, Department of Emergency, Lanzhou University
Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, China
E-Mail: lipeiw@lzu.edu.cn
Copyright ©2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the
CC-BY-NC-ND license. This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
permissible to download and share the work provided it is properly cited. The work cannot be
changed in any way or used commercially without permission from the journal.
Chinese Medical Journal 2021;134(21)
Received: 09-11-2020 Edited by: Jing Ni
Access this article online
Quick Response Code: Website:
www.cmj.org
DOI:
10.1097/CM9.0000000000001594
Medical Progress
2547
pancreatic infection and sepsis.
[2,5,9]
Thus, it is very
meaningful to protect the intestinal damage during SAP.
Autophagy acts as a double-edged sword in the gut. The
various roles of autophagy in regulating homeostasis and
inammation are extremely signicant in the context of the
intestinal mucosa, where most of the stressors are likely to
converge.
[3]
According to current researches, autophagy is
controlled by almost all types of pattern recognition
receptors and is also regulated by cytokines and receptors
of innate immunity and adaptive immunity. This means
that autophagy actively or passively participates in several
regulatory pathways, whether in chronic inammation
of the intestine or SAP, which is why researchers are
particularly interested in its role in the intestinal muco-
sa.
[4,5]
At present, the main functions of autophagy in
intestinal mucosal homeostasis are as follows. (1) Elimi-
nate invading microorganisms and toxins. Autophagy can
be initiated during the process of host cells taking up
bacteria or macrophages actively engulng bacteria. Other
studies reported that Atg5 contributed to antibiosis,
especially by increasing susceptibility to infection and
controlling dissemination of Listeria monocytogenes,
Mycobacterium tuberculosis, and Salmonella.
[8,10]
More-
over, autophagy facilitates the binding of endogenous
antigens with major histocompatibility complex-II mole-
cules that are recognized by a cluster of differentiation 4
+
T
cells.
[4]
Autophagy can also sense viral RNA and DNA in
the cytoplasm through retinoic acid inducible gene I and
cyclic guanosine monophosphate-anti-microbial peptide
synthetase, thereby inhibiting the production of type I
interferon (IFN-I). The effect is to enhance the resistance of
the intestine to the virus.
[3,7]
(2) Protect the TJs and GJs
vesicle turnover of the intestine. Change in paracellular TJs
proteins is the main factor that increases intestinal
permeability in SAP.
[1]
Studies have shown that autophagy
can increase the TJs barrier function in Caco-2 intestinal
stem cells (IECs) by enhancing Claudin-2 (a cation-
selective pore-forming protein that plays an important
role in TJs and the intestinal barrier) proteins lysosomal
degradation.
[7]
Autophagy can also degrade other abnor-
mal TJ proteins to prevent the release of intestinal toxins
and pro-inammatory cytokines.
[1,2]
It was recently shown
that defects in mitochondria and ER functions induce
intestinal permeability, promoting Escherichia coli inter-
nalization and transcytosis across the epithelium, and these
are counteracted by selective autophagy-mediated elimi-
nation of intracellular bacteria, which is so-called
xenophagy.
[8]
However, uncontrolled autophagy can
destroy the structure of TJs proteins because of excessive
degradation, ultimately leading to apoptosis.
[2]
(3) Main-
tain the secretion of Paneth cells (PC) and goblet cells. A
study showed that autophagy can maintain the secretory
function of PC.
[6]
Many autophagy-related genes, includ-
ing nucleotide-binding oligomerization domain 2, autoph-
agy-related protein16L1 (ATG16L1), leucine-rich repeat
kinase 2, and X-box binding protein 1, exert various effects
on PC.
[11]
Moreover, autophagy controls the development
and function of goblet cells, and the ATG16L1
T300A
polymorphism alters goblet cell morphology.
[10]
Autoph-
agy deciency (eg, Atg5,Atg7, and LC3) in goblet cells
reduced mucin production by affecting ROS generation
and calcium release from the ER.
[8]
(4) Balance the immune
response of the intestine. Macrophages, DCs, T cells, B
cells, and natural killer cells are the important components
of the intestinal mucosal immune system. A growing body
of evidence has emerged supporting the view that
autophagy mediates the crucial functions of triggering
and modulating innate and adaptive immune responses
such as antigen presentation, cytokines secretion, and
antimicrobial peptide production.
[3]
Autophagy can affect
the cytoskeleton or organization of DCs and can also
indirectly affect the activation of T cells. The reduction in
autophagy levels leads to reduced antigen sampling and
interleukin-10 (IL-10) secretion, increased DCs matura-
tion, and increased T-cell proliferation and production of
pro-inammatory type of DCs, which will cause the
overgrowth of intestinal bacteria and increase the risk of
bacteria being freed from the intestinal cavity.
[3,8]
(5)
Regulate ROS and inammation. Autophagy, especially
mitophagy, by eliminating damaged or superuous
mitochondria, plays a major role in limiting ROS
accumulation. Mutations in the autophagy-related genes
or autophagy deciency have an impact on ROS levels via
the impaired elimination of dysfunctional mitochondria in
several cell types.
[6]
Understanding the role of autophagy
and oxidative stress in SAP-induced intestinal mucosal
injury is critical for the development of new therapeutic
strategies.
[1]
Excessive inammation is also a key factor in
intestinal damage. High-mobility group box-1 (HMGB1),
the key inammatory mediator, has a conrmed associa-
tion with SAP. Studies observed that HMGB1 inhibition
ameliorated the disruption of TJs and autophagy exhibited
in SAP and adjusted oxidative stress to maintain the
internal environment.
[2]
Kim et al
[6]
showed that
ATG16L1-decient macrophages exhibited Toll/IL-1 re-
ceptor domain-containing adaptor or inducing IFN-b
dependent activation of the inammasome, resulting in the
production of high amounts of the inammatory cytokines
such as IL-1band IL-18. Thus, it has been demonstrated
that autophagy can modulate cytokine-induced pro-
grammed cell death in intestinal epithelium, limiting
intestinal inammation.
[8]
(6) Produce antibrosis effects.
Autophagy mainly promotes the degradation of broblast
collagen to exert antibrotic effects. When autophagy is
inhibited, it will aggravate brosis. But the degree of
brosis is related to the level of autophagy in different
organ environments. Other studies observed that autoph-
agy seems to inhibit intestinal brosis by modulating the
function of the innate immune system and the mesenchy-
mal activity.
[3,12]
(7) Balance intestinal epithelial cells
(ISCs) regeneration. The critical role of autophagy in
maintaining ISC functions under different physiological
conditions has been discovered only in recent years. Recent
work has suggested that deletion of the Atg5 gene in
intestinal epithelial cells results in accumulation of
mitochondria and ROS in leucine-rich repeat-containing
G protein-coupled receptor 5 (Lgr5) ISCs and impaired
their capacity to induce intestinal regeneration following
irradiation. Subsequently, researchers show that loss of
Atg7 induces the p53-mediated apoptosis of Lgr5
+
ISCs.
[13]
Wu et al
[7]
also pointed out that intrinsic
autophagy supported ISCs maintenance and promoted
the recovery of IECs after radiation-induced injuries. It is
suggested that autophagy may play an important role in
inducing the self-renewal of ISCs in intestines.
[2,10]
Chinese Medical Journal 2021;134(21) www.cmj.org
2548
In view of the importance of autophagy in various diseases,
researchers have great interest in developing potential
treatments to regulate this pathway. The disaccharide
trehalose, which increases the efciency of autophagy,
reduces pancreatic injury and AP severity in animal models
and holds promise as a potential therapeutic agent in AP.
[5]
Chloroquine (CQ) and its derivatives have been widely
used to inhibit autophagy in vitro with the benetof
relatively low toxicity. In the dextran sulfate sodium-
induced murine colitis model, CQ administration signi-
cantly retarded colon length shortening, inammatory cell
inltration, tissue damage, and body weight loss.
[7]
Similarly, it was reported that glutamine enhances
autophagy in IECs both under basal and stress-induced
conditions by regulating mTOR and mitogen-activated
protein kinase/p38 pathways, thus limiting stress-induced
cellular apoptosis.
[8]
In addition, recent studies suggested
that bone marrow-derived mesenchymal stem cells sup-
pressed autophagy in multiple organs (including the
pancreas, small intestine, and lungs) to protect against
SAP-induced multiple-organ injury.
[14]
In the future, with
the deepening of related research, we believe that more
targeted drugs will be developed.
Patients who survive the SAP process often have some
sequelae, such as diabetes, pancreatic exocrine insufcien-
cy, and chronic pancreatitis. At the same time, the high
incidence of AP also highlights the urgent need for new
treatment methods. The role of autophagy in various
diseases has shown exciting results and has become a new
research eld. However, the mechanism of autophagy in
intestinal homeostasis and the potential effects during SAP
still require more researches. We hope this review provide a
comprehensive perspective revealing the role of autophagy
modulators in diseases and opening up a new world for the
treatment of SAP.
Funding
This work is supported by a grant from the Lanzhou Talent
Innovation and Entrepreneurship Project (No. 2016-RC-52).
Conicts of interest
None.
References
1. Huang L, Jiang Y, Sun Z, Gao Z, Wang J, Zhang D. Autophagy
strengthens intestinal mucosal barrier by attenuating oxidative stress
in severe acute pancreatitis. Dig Dis Sci 2018;63:910919. doi:
10.1007/s10620-018-4962-2.
2. Huang L, Zhang D, Han W, Guo C. High-mobility group box-1
inhibition stabilizes intestinal permeability through tight junctions in
experimental acute necrotizing pancreatitis. Inamm Res 2019;
68:677689. doi: 10.1007/s00011-019-01251-x.
3. Haq S, Grondin J, Banskota S, Khan WI. Autophagy: roles in
intestinal mucosal homeostasis and inammation. J Biomed Sci
2019;26:19. doi: 10.1186/s12929-019-0512-2.
4. Saha S, Panigrahi DP, Patil S, Bhutia SK. Autophagy in health and
disease: a comprehensive review. Biomed Pharmacother 2018;104:
485495. doi: 10.1016/j.biopha.2018.05.007.
5. Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat
Rev Gastroenterol Hepatol 2019;16:479496. doi: 10.1038/s41575-
019-0158-2.
6. Kim S, Eun HS, Jo EK. Roles of autophagy-related genes in the
pathogenesis of inammatory bowel disease. Cells 2019;8:77. doi:
10.3390/cells8010077.
7. Wu Y, Tang L, Wang B, Sun Q, Zhao P, Li W. The role of autophagy
in maintaining intestinal mucosal barrier. J Cell Physiol 2019;
234:1940619419. doi: 10.1002/jcp.28722.
8. Larabi A, Barnich N, Nguyen HTT. New insights into the interplay
between autophagy, gut microbiota and inammatory responses in
IBD. Autophagy 2020;16:3851. doi: 10.1080/15548627.2019.
1635384.
9. Landahl P, Ansari D, Andersson R. Severe acute pancreatitis: gut
barrier failure, systemic inammatory response, acute lung injury,
and the role of the mesenteric lymph. Surg Infect (Larchmt)
2015;16:651656. doi: 10.1089/sur.2015.034.
10. Lassen KG, Xavier RJ. Mechanisms and function of autophagy in
intestinal disease. Autophagy 2018;14:216220. doi: 10.1080/
15548627.2017.1389358.
11. Yang E, Shen J. The roles and functions of Paneth cells in Crohns
disease: a critical review. Cell Prolif 2021;54:e12958. doi: 10.1111/
cpr.12958.
12. Cosin-Roger J, Canet F, Macias-Ceja DC, Gisbert-Ferrandiz L, Ortiz-
Masia D, Esplugues JV, et al. Autophagy stimulation as a potential
strategy against intestinal brosis. Cells 2019;8:1078. doi: 10.3390/
cells8091078.
13. Trentesaux C, Fraudeau M, Pitasi CL, Lemarchand J, Jacques S,
Duche A, et al. Essential role for autophagy protein ATG7 in the
maintenance of intestinal stem cell integrity. Proc Natl Acad Sci U S A
2020;117:1113611146. doi: 10.1073/pnas.1917174117.
14. Song G, Liu D, Geng X, Ma Z, Wang Y, Xie W, et al. Bone marrow-
derived mesenchymal stem cells alleviate severe acute pancreatitis-
induced multiple-organ injury in rats via suppression of autophagy.
Exp Cell Res 2019;385:111674. doi: 10.1016/j.yexcr.2019.111674.
How to cite this article: Li HY, Lin YJ, Zhang L, Zhao J, Xiao DY, Li PW.
Autophagy in intestinal injury caused by severe acute pancreatitis. Chin
Med J 2021;134:25472549. doi: 10.1097/CM9.0000000000001594
Chinese Medical Journal 2021;134(21) www.cmj.org
2549
... During the development of sepsis, the functions of intestinal barriers are altered. Impaired intestinal barriers allow for the invasion of intestinal bacteria and entry of endotoxins into the blood and lymph circulation, eventually causing a "second attack" and secondary pancreatic infection and sepsis (Li H. Y. et al., 2021). Candida albicans (C. ...
... Candida albicans (C. albicans) is a member of the intestinal commensal microbiota that colonizes on the mucosal surfaces of the gastrointestinal tract (Jenull et al., 2021;Li H. Y. et al., 2021). This yeast can translocate into the bloodstream through impaired gut barriers in susceptible individuals, such as patients with sepsis, resulting in opportunistic infections (Hirao et al., 2014). ...
Article
Full-text available
Colonization of the intestinal tract by Candida albicans ( C. albicans ) can lead to invasive candidiasis. Therefore, a functional intestinal epithelial barrier is critical for protecting against invasive C. albicans infections. We collected fecal samples from patients with Candida albicans bloodstream infection and healthy people. Through intestinal flora 16sRNA sequencing and intestinal metabolomic analysis, we found that C. albicans infection resulted in a significant decrease in the expression of the metabolite kynurenic acid (KynA). We used a repeated C. albicans intestinal infection mouse model, established following intake of 3% dextran sulfate sodium salt (DSS) for 9 days, and found that KynA, a tryptophan metabolite, inhibited inflammation, promoted expression of intestinal tight junction proteins, and protected from intestinal barrier damage caused by invasive Candida infections. We also demonstrated that KynA activated aryl hydrocarbon receptor (AHR) repressor in vivo and in vitro . Using Caco-2 cells co-cultured with C. albicans , we showed that KynA activated AHR, inhibited the myosin light chain kinase-phospho-myosin light chain (MLCK-pMLC) signaling pathway, and promoted tristetraprolin (TTP) expression to alleviate intestinal inflammation. Our findings suggest that the metabolite KynA which is differently expressed in patients with C. albicans infection and has a protective effect on the intestinal epithelium, via activating AHR, could be explored to provide new potential therapeutic strategies for invasive C. albicans infections.
Article
Full-text available
Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α‐defensins, human α‐defensin 5 (HD‐5) and human α‐defensin 6 (HD‐6) in response to bacterial, cholinergic and other stimuli. The α‐defensins are broad‐spectrum microbicides that play critical roles in controlling gut microbiota and maintaining intestinal homeostasis. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is a complicated autoimmune disorder. The pathogenesis of CD involves genetic factors, environmental factors and microflora. Surprisingly, with regard to genetic factors, many susceptible genes and pathogenic pathways of CD, including nucleotide‐binding oligomerization domain 2 (NOD2), autophagy‐related 16‐like 1 (ATG16L1), immunity‐related guanosine triphosphatase family M (IRGM), wingless‐related integration site (Wnt), leucine‐rich repeat kinase 2 (LRRK2), histone deacetylases (HDACs), caspase‐8 (Casp8) and X‐box‐binding protein‐1 (XBP1), are relevant to PCs. As the underlying mechanisms are being unravelled, PCs are identified as the central element of CD pathogenesis, integrating factors among microbiota, intestinal epithelial barrier dysfunction and the immune system. In the present review, we demonstrate how these genes and pathways regulate CD pathogenesis via their action on PCs and what treatment modalities can be applied to deal with these PC‐mediated pathogenic processes.
Article
Full-text available
We recently observed reduced autophagy in Crohn’s disease patients and an anti-inflammatory effect of autophagy stimulation in murine colitis, but both anti- and pro-fibrotic effects are associated with autophagy stimulation in different tissues, and fibrosis is a frequent complication of Crohn’s disease. Thus, we analyzed the effects of pharmacological modulation of autophagy in a murine model of intestinal fibrosis and detected that autophagy inhibition aggravates, while autophagy stimulation prevents, fibrosis. These effects are associated with changes in inflammation and in collagen degradation in primary fibroblasts. Thus, pharmacological stimulation of autophagy may be useful against intestinal fibrosis.
Article
Full-text available
One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using in vitro and in vivo models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation, appropriate intestinal immune responses and anti-microbial protection. This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria. A better understanding of the role of autophagy in IBD pathogenesis may provide better sub-classification of IBD phenotypes and novel approaches for disease management. Abbreviations: AIEC: adherent-invasive Escherichia coli; AMPK: AMP-activated protein kinase; ATF6: activating transcription factor 6; ATG: autophagy related; Atg16l1[ΔIEC] mice: mice with Atg16l1 depletion specifically in intestinal epithelial cells; Atg16l1[HM] mice: mice hypomorphic for Atg16l1 expression; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; CALCOCO2: calcium binding and coiled-coil domain 2; CASP: caspase; CD: Crohn disease; CGAS: cyclic GMP-AMP synthase; CHUK/IKKA: conserved helix-loop-helix ubiquitous kinase; CLDN2: claudin 2; DAPK1: death associated protein kinase 1; DCs: dendritic cells; DSS: dextran sulfate sodium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK: eukaryotic translation initiation factor 2 alpha kinase; ER: endoplasmic reticulum; ERBIN: Erbb2 interacting protein; ERN1/IRE1A: ER to nucleus signaling 1; FNBP1L: formin binding protein 1-like; FOXP3: forkhead box P3; GPR65: G-protein coupled receptor 65; GSK3B: glycogen synthase kinase 3 beta; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IFN: interferon; IL: interleukin; IL10R: interleukin 10 receptor; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LAMP1: lysosomal-associated membrane protein 1; LAP: LC3-associated phagocytosis; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; LRRK2: leucine-rich repeat kinase 2; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex; MIF: macrophage migration inhibitory factor; MIR/miRNA: microRNA; MTMR3: myotubularin related protein 3; MTOR: mechanistic target of rapamycin kinase; MYD88: myeloid differentiation primary response gene 88; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NPC: Niemann-Pick disease type C; NPC1: NPC intracellular cholesterol transporter 1; OMVs: outer membrane vesicles; OPTN: optineurin; PI3K: phosphoinositide 3-kinase; PRR: pattern-recognition receptor; PTPN2: protein tyrosine phosphatase, non-receptor type 2; PTPN22: protein tyrosine phosphatase, non-receptor type 22 (lymphoid); PYCARD/ASC: PYD and CARD domain containing; RAB2A: RAB2A, member RAS oncogene family; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RIPK2: receptor (TNFRSF)-interacting serine-threonine kinase 2; ROS: reactive oxygen species; SNPs: single nucleotide polymorphisms; SQSTM1: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Th: T helper 1; TIRAP/TRIF: toll-interleukin 1 receptor (TIR) domain-containing adaptor protein; TLR: toll-like receptor; TMEM173/STING: transmembrane protein 173; TMEM59: transmembrane protein 59; TNF/TNFA: tumor necrosis factor; Treg: regulatory T; TREM1: triggering receptor expressed on myeloid cells 1; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type; XBP1: X-box binding protein 1; XIAP: X-linked inhibitor of apoptosis.
Article
Full-text available
Background In acute necrotizing pancreatitis (ANP), bacterial translocation (BT) from the gastrointestinal tract is the essential pathogenesis in the development of septic complications. Although high-mobility group box-1 (HMGB1) is associated with BT and organ dysfunction in ANP, the mechanism of HMGB1 in the intestinal barrier dysfunction and BT has not been well addressed. In this study, we intend to address the role of HMGB1 in ANP involving BT and intestinal barrier dysfunction. Methods Experimental ANP was achieved in male Sprague–Dawley rats through a retrograde injection of taurocholate into the common biliopancreatic duct following a laparotomy operation. HMGB1 blockade intervention was conducted with a subcutaneous injection of anti-HMGB1 antibody immediately before the laparotomy procedure. Twenty-four hours after ANP induction, pancreatic and intestinal tissues and blood samples were collected for a histopathological assessment and lipid peroxidation or glutathione (GSH) evaluation. AP-induced barrier dysfunction was determined by an intestinal permeability assessment. Tight junction proteins and autophagy regulators were investigated by western blotting, immunohistological analysis and confocal immunofluorescence imaging. Results ANP developed as indicated by microscopic parenchymal necrosis and fat necrosis, which were associated with intestinal mucosal barrier dysfunction. HMGB1 inhibition played a protective role in intestinal mucosal barrier dysfunction, protected against microbiome changes in ANP, and relieved intestinal oxidative stress. Additionally, HMGB1 inhibition attenuated intestinal permeability; preserved the expression of TJs, such as claudin-2 and occludin; and decreased autophagy. Furthermore, the autophagy regulator LC3 and TJ protein claudin-2 were both upregulated in ANP according to dual immunofluorescence analysis. Conclusion HMGB1 inhibition ameliorated the severity of experimental ANP though beneficial effects on BT, mainly involving in TJ function.
Article
Full-text available
Abstract The intestinal mucosa is a site of multiple stressors and forms the barrier between the internal and external environment. In the intestine, a complex interplay between the microbiota, epithelial barrier and the local immune system maintains homeostasis and promotes a healthy gut. One of the major cellular catabolic processes that regulate this homeostasis is autophagy. Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response. Dysregulation of the autophagy process causes disruption of several aspects of the intestinal epithelium and the immune system that can lead to an inappropriate immune response and subsequent inflammation. Genome-wide association studies have found an association between several risk loci in autophagy genes and inflammatory bowel disease. The aim of the current review is to provide an update on the role of autophagy in intestinal mucosal physiology and in the control of inappropriate inflammation.
Article
Full-text available
Autophagy is an intracellular catabolic process that is essential for a variety of cellular responses. Due to its role in the maintenance of biological homeostasis in conditions of stress, dysregulation or disruption of autophagy may be linked to human diseases such as inflammatory bowel disease (IBD). IBD is a complicated inflammatory colitis disorder; Crohn’s disease and ulcerative colitis are the principal types. Genetic studies have shown the clinical relevance of several autophagy-related genes (ATGs) in the pathogenesis of IBD. Additionally, recent studies using conditional knockout mice have led to a comprehensive understanding of ATGs that affect intestinal inflammation, Paneth cell abnormality and enteric pathogenic infection during colitis. In this review, we discuss the various ATGs involved in macroautophagy and selective autophagy, including ATG16L1, IRGM, LRRK2, ATG7, p62, optineurin and TFEB in the maintenance of intestinal homeostasis. Although advances have been made regarding the involvement of ATGs in maintaining intestinal homeostasis, determining the precise contribution of autophagy has remained elusive. Recent efforts based on direct targeting of ATGs and autophagy will further facilitate the development of new therapeutic opportunities for IBD.
Article
The intestinal epithelium acts as a barrier between the organism and its microenvironment, including the gut microbiota. It is the most rapidly regenerating tissue in the human body thanks to a pool of intestinal stem cells (ISCs) expressing Lgr5 . The intestinal epithelium has to cope with continuous stress linked to its digestive and barrier functions. Epithelial repair is crucial to maintain its integrity, and Lgr5-positive intestinal stem cell (Lgr5 ⁺ ISC) resilience following cytotoxic stresses is central to this repair stage. We show here that autophagy, a pathway allowing the lysosomal degradation of intracellular components, plays a crucial role in the maintenance and genetic integrity of Lgr5 ⁺ ISC under physiological and stress conditions. Using conditional mice models lacking the autophagy gene Atg7 specifically in all intestinal epithelial cells or in Lgr5 ⁺ ISC, we show that loss of Atg7 induces the p53-mediated apoptosis of Lgr5 ⁺ ISC. Mechanistically, this is due to increasing oxidative stress, alterations to interactions with the microbiota, and defective DNA repair. Following irradiation, we show that Lgr5 ⁺ ISC repair DNA damage more efficiently than their progenitors and that this protection is Atg7 dependent. Accordingly, we found that the stimulation of autophagy on fasting protects Lgr5 ⁺ ISC against DNA damage and cell death mediated by oxaliplatin and doxorubicin treatments. Finally, p53 deletion prevents the death of Atg7 -deficient Lgr5 ⁺ ISC but promotes genetic instability and tumor formation. Altogether, our findings provide insights into the mechanisms underlying maintenance and integrity of ISC and highlight the key functions of Atg7 and p53.
Article
Patients with severe acute pancreatitis (SAP) represent a substantial challenge to medical practitioners due to the high associated rates of morbidity and mortality and a lack of satisfactory therapeutic outcomes. In a previous study, our group demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate SAP; however, the mechanisms of action remain to be fully understood. BMSCs were intravenously injected into SAP rats 12 h after experimental induction of SAP using sodium taurocholate (NaT). Histopathological changes and the levels of pro-inflammatory mediators were assessed by hematoxylin and eosin (H&E) staining and ELISA, respectively. Autophagy levels were assessed using qRT-PCR, western blotting, immunohistochemistry, immunofluorescence, and transmission electron microscopy. AR42J cells and human umbilical vein endothelial cells (HUVECs) were administered BMSC-conditioned media (BMSC-CM) after NaT treatment, and cell viability was measured using a Cell Counting Kit-8 (CCK-8) and flow cytometry. In vivo, BMSCs effectively reduced multiple systematic inflammatory responses, suppressed the activation of autophagy, and improved intestinal dysfunction. In vitro, BMSC-CM significantly improved the viability of injured cells, promoted angiogenesis, and decreased autophagy. We therefore propose that the administration of BMSCs alleviates SAP-induced multiple organ injury by inhibiting autophagy.
Article
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
Article
The intestinal mucosal barrier is the first line to defense against luminal content penetration and performs numerous biological functions. The intestinal epithelium contains a huge surface that is lined by a monolayer of intestinal epithelial cells (IECs). IECs are dominant mediators in maintaining intestinal homeostasis that drive diverse functions including nutrient absorption, physical segregation, secretion of antibacterial peptides, and modulation of immune responses. Autophagy is a cellular self‐protection mechanism in response to various stresses, and accumulating studies have revealed its importance in participating physiological processes of IECs. The regulatory effects of autophagy depend on the specific IEC types. This review aims to elucidate the myriad roles of autophagy in regulating the functions of different IECs (stem cells, enterocytes, goblet cells, and Paneth cells), and present the progress of autophagy‐targeting therapy in intestinal diseases. Understanding the involved mechanisms can provide new preventive and therapeutic strategies for gastrointestinal dysfunction and diseases. Autophagy plays a pivotal role in the development, differentiation, and functions of intestinal epithelial cells. Thus it is crucial for the maintenance of the intestinal mucosal barrier and homeostasis.