Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis

Barrera, Kaylene; Stanek, Albert; Okochi, Kei; Niewiadomska, Zuzanna; Mueller, Cathy M.; Ou, Peiqi; John, Devon; Alfonso, Antonio E.; Tenner, Scott; Huan, Chongmin

doi:10.4291/wjgp.v9.i2.37

Cited by 23 publications

(24 citation statements)

References 82 publications

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“…ERS is implicated as a cause of inflammation in many disorders and reported to be associated with intestinal barrier dysfunction in inflammatory bowel diseases (19). Accumulating evidence supports that ERS in the pancreas is a driving force behind the pathogenesis of ANP (20), but how ERS in the intestine works in ANP is rarely explored. One study (21) suggested that ERS was induced in the ileal epithelia during 3% sodium taurocholate-induced pancreatitis, indicated by an irregular, dilated endoplasmic reticulum and Bip upregulation.…”

Section: Discussionmentioning

confidence: 99%

Commensal Escherichia coli Aggravates Acute Necrotizing Pancreatitis through Targeting of Intestinal Epithelial Cells

Zheng

Lou

Fan

et al. 2019

Appl Environ Microbiol

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An increase of Escherichia-Shigella was previously reported in acute necrotizing pancreatitis (ANP). We investigated whether Escherichia coli MG1655, an Escherichia commensal organism, increased intestinal injury and aggravated ANP in rats. ANP was induced by retrograde injection of 3.5% sodium taurocholate into the biliopancreatic duct. Using gut microbiota-depleted rats, we demonstrated that gut microbiota was involved in the pancreatic injury and intestinal barrier dysfunction in ANP. Using 16S rRNA gene sequencing and quantitative PCR, we found intestinal dysbiosis and a significant increase of E. coli MG1655 in ANP. Afterward, administration of E. coli MG1655 by gavage to gut microbiota-depleted rats with ANP was performed. We observed that after ANP induction, E. coli MG1655-monocolonized rats presented more severe injury in the pancreas and intestinal barrier function than gut microbiota-depleted rats. Furthermore, Toll-like receptor 4 (TLR4)/MyD88/p38 mitogen-activated protein (MAPK) and endoplasmic reticulum stress (ERS) activation in intestinal epithelial cells were also increased more significantly in the MG1655-monocolonized ANP rats. In vitro, the rat ileal epithelial cell line IEC-18 displayed aggravated tumor necrosis factor alpha-induced inflammation and loss of tight-junction proteins in coculture with E. coli MG1655, as well as TLR4, MyD88, and Bip upregulation. In conclusion, our study shows that commensal E. coli MG1655 increases TLR4/MyD88/p38 MAPK and ERS signaling-induced intestinal epithelial injury and aggravates ANP in rats. Our study also describes the harmful potential of commensal E. coli in ANP. IMPORTANCE This study describes the harmful potential of commensal E. coli in ANP, which has not been demonstrated in previous studies. Our work provides new insights into gut bacterium-ANP cross talk, suggesting that nonpathogenic commensals could also exhibit adverse effects in the context of diseases.

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Section: Discussionmentioning

confidence: 99%

Commensal Escherichia coli Aggravates Acute Necrotizing Pancreatitis through Targeting of Intestinal Epithelial Cells

Zheng

Lou

Fan

et al. 2019

Appl Environ Microbiol

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“…Previous studies targeting ER stress regulatory molecules have shed light on their effects on pancreatic function and disease pathology and have uncovered a balance between protective (eg, IRE1/XBP1s) and pathologic (PERK/ATF4/CHOP) UPR in pancreatic physiology and disease. 5 , 9 , 11 , 28 The present study shows marked up-regulation and/or dysregulation of pathologic cellular pathways including PERK, CHOP, and c-jun N-terminal kinase with loss of AT-1; however, the CP observed in Ela-Cre AT-1 -/- appeared to be relatively mild to moderate, suggesting a capability of acinar cells to adapt to chronic ER stress when the protective IRE1/XBP1s UPR is intact. Interestingly, it was shown previously that AT-1 expression may be downstream of IRE1/XBP1s, suggesting that AT-1 also may play a role in the protective ER stress response 21 ; this is supported further by the finding that AT-1 expression increases at the initiation of pancreatitis, but is down-regulated as the disease progresses.…”

Section: Discussionmentioning

confidence: 52%

“…The UPR is a well-studied set of cellular pathways designed to monitor and respond to the accumulation of proteins within the endoplasmic reticulum (ER) lumen. 2 , 4 , 5 There are 3 protein sensors, in brief: inositol-requiring enzyme 1 (IRE1), which produces a spliced variant of the transcription factor X-box binding protein 1 (XBP1s), activating transcription factor (ATF)6, and protein kinase R-like ER kinase (PERK), which phosphorylates elongation initiation factor 2α (eIF2α). Both XBP1s and ATF6 act to expand the ER and enhance protein folding capabilities, while eIF2α phosphorylation inhibits cap-dependent protein translation, reducing ER input.…”

mentioning

confidence: 99%

Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

Cooley¹,

Thomas²,

Deans³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Pathologic activation of the unfolded protein response is a key event in the development of pancreatitis. Impairing the endoplasmic reticulum acetyl-CoA transporter AT-1 in acini leads to chronic overactivation of the unfolded protein response and presents a spontaneous chronic pancreatitis phenotype. BACKGROUND & AIMS: Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated posttranslational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis. METHODS: We used an AT-1 S113R/þ hypomorphic mouse model, and generated an inducible, acinar-specific, AT-1 knockout mouse model, and performed histologic and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology. RESULTS: We found that AT-1 expression is down-regulated significantly during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the spliced x-box binding protein 1 and protein kinase R-like ER kinase pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute-on-chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy. CONCLUSIONS: These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response, and that perturbations in AT-1 function leads to pancreatic disease.

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“…Endoplasmic reticulum stress can also trigger necroptosis. According to reports, many unfolded or misfolded proteins accumulate in the endoplasmic reticulum, when acinar cells are challenged by injury or other stresses 35,36 . In our research, we innovatively demonstrated that rSAA3 could promote CCK‐induced acinar cell necroptosis, but whether this is a direct or indirect effect remains unknown.…”

Section: Discussionmentioning

confidence: 75%

Serum amyloid A3 is required for caerulein‐induced acute pancreatitis through induction of RIP3‐dependent necroptosis

Yang

et al. 2020

Immunol Cell Biol

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Serum amyloid A (SAA) is an early and sensitive biomarker of inflammatory diseases, but its role in acute pancreatitis (AP) is still unclear. Here, we used a caerulein‐induced mouse model to investigate the role of SAA in AP and other related inflammatory responses. In our study, we found that the expression of a specific SAA isoform, SAA3, was significantly elevated in a caerulein‐induced AP animal model. In addition, SAA3‐knockout (Saa3−/−) mice showed lower serum levels of amylase and lipase, tissue damage and proinflammatory cytokine production in the pancreas compared with those of wild‐type mice in response to caerulein administration. AP‐associated acute lung injury was also significantly attenuated in Saa3−/− mice. In our in vitro experiments, treatment with cholecystokinin and recombinant SAA3 significantly induced necroptosis and cytokine production. Moreover, we found that the regulatory effect of SAA3 on acinar cell necroptosis was through a receptor‐interacting protein 3 (RIP3)‐dependent manner. Collectively, our findings indicate that SAA3 is required for AP by inducing an RIP3‐dependent necroptosis pathway in acinar cells and is a potential drug target for AP.

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Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis

Cited by 23 publications

References 82 publications

Commensal Escherichia coli Aggravates Acute Necrotizing Pancreatitis through Targeting of Intestinal Epithelial Cells

Commensal Escherichia coli Aggravates Acute Necrotizing Pancreatitis through Targeting of Intestinal Epithelial Cells

Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

Serum amyloid A3 is required for caerulein‐induced acute pancreatitis through induction of RIP3‐dependent necroptosis

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