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Epithelial-immune cell crosstalk during injury and recovery in acute pancreatitis

急性胰腺炎损伤和恢复过程中上皮-免疫细胞的串扰

基本信息

批准号：
10363904
负责人：
Timothy Louis Frankel
金额：
$ 44.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-22 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363904
关键词：
3-Dimensional Acinar Cell Acinus organ component Admission activity Affinity Anabolism Anti-Inflammatory Agents Area Arginine Autocrine Communication Autophagocytosis Binding Binding Proteins Biochemical Biology Cell Line Cells Cessation of life Cholecystokinin Clinical Communication Data Dendritic Cells Development Disease Disease Progression Dose Drops Enzymes Epithelial Epithelial Cells Equilibrium Flow Cytometry Gastroenterologist Gastrointestinal tract structure Genes Goals Histologic Homeostasis Hospitalization Host Defense Human Immune Immune signaling Immunity In Vitro Inflammation Inflammatory Injury Knock-out Knockout Mice Knowledge Malignant - descriptor Measures Mediator of activation protein Metabolism Methods Mouse Protein Mus Natural regeneration Organ Organ failure Pancreas Pancreatic Diseases Pancreatic Injury Pancreatitis Paracrine Communication Pharmacology Physicians Physiology Prevalence Production Protein Secretion Recovery Research Personnel Research Proposals Retinoic Acid Receptor Role Sampling Scientist Serum Severities Signal Pathway Signal Transduction Sorting - Cell Movement Source Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Tretinoin United States acute pancreatitis analog autocrine base biobank cell injury clinically relevant cohort cost cytokine experience gastrointestinal improved in vivo injury and repair injury recovery insight interleukin-22 mouse model necrotic tissue novel organ repair overexpression oxidation paracrine prevent protein expression receptor response response to injury single-cell RNA sequencing tissue injury tissue repair

项目摘要

Acute pancreatitis (AP), an inflammatory disorder of the pancreas, is the most common gastrointestinal condition requiring hospitalization in the United States resulting in 275,000 hospital admissions annually. While many suffer only mild illness, some progress to severe AP characterized by multisystem organ failure and death. Intact immunity is vital for tissue protection and recovery from AP and data suggests that imbalance in pro and anti- inflammatory cytokines may underlie progression of disease. Evidence exists of communication between immune and epithelial cells in the pancreatic microenvironment but its role in AP remains understudied and further understating is needed to identify potential therapies aimed at enhancing organ repair. Interleukin-22 (IL22) has emerged as an important cytokine in host defense and tissue repair within the gastrointestinal tract and is often active in areas of inflammation. Previous studies and our own data have shown that IL22 signaling reduces tissue damage during AP by mechanisms related to autophagy. IL22 binding protein (IL22BP), a soluble neutralizing receptor, suppresses IL22 activity, and functions to maintain homeostasis. Only recently discovered, it is released from dendritic cells (DC) in response to retinoic acid stimulation and binds to IL22 with very high affinity. Induction of AP in mice using the cholecystokinin analogue cerulein results in a significant drop in IL22BP, suggesting it may serve as an adaptive response to tissue injury, enhancing protective IL22 signaling. Further supporting this is the markedly reduced pancreatic damage in transgenic mice lacking IL22BP given similar doses of cerulein. The goal of this proposal is to improve our understand of how IL22 signaling is regulated in AP through changes in expression of IL22BP. This is important as we have previously demonstrated that continued overexpression of IL22 is associated with malignant transformation in the pancreas. Our central hypothesis is that tissue injury in AP leads to an adaptive decrease in IL22BP which results from changes in RA metabolism. A return of IL22BP expression after recovery results in homeostatic suppression of IL22 signaling. We will test this hypothesis using transgenic mouse models and serum samples from a human AP cohort. Specific aim 1 will determine the mechanisms underlying the observed decreased tissue damage experienced by IL22BP-/- mice subjected to AP. We will explore changes in IL22 signaling, particularly related to autophagy and enhancement of genes involved in regeneration. Based on preliminary data that a key RA producing enzyme, ALDH1A1, is markedly reduced in AP, specific aim 2 will further characterize retinoic acid metabolism in the pancreas during injury and recovery. This will include in vivo studies using pharmacologic measures to inhibit RA anabolism with the goal of further reducing IL22BP production. Specific aim 3 will explore the crosstalk between acinar and immune cells and the role of autocrine and paracrine signaling of RA in DC production of IL22BP. Use of RA receptor blockade will be explored as a clinically relevant method to further reduce the adaptive decrease in IL22BP during AP, enhancing tissue recovery and preventing progression to severe AP.

急性胰腺炎（AP）是胰腺的一种炎症性疾病，是最常见的胃肠道疾病