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.

胰腺炎性疾病急性胰腺炎（AP）是最常见的胃肠道状况在美国需要住院，每年导致275,000次住院。而很多仅患有轻度疾病，以多系统器官衰竭和死亡为特征的严重AP进展。完好无损的免疫力对于组织保护和从AP中恢复至关重要，数据表明，Pro和抗抗的不平衡炎性细胞因子可能是疾病进展的基础。存在证据胰腺微环境中的免疫和上皮细胞，但其在AP中的作用仍在研究中，并且需要进一步低估以确定旨在增强器官维修的潜在疗法。白介素22 （IL22）在胃肠道内的宿主防御和组织修复中已成为重要的细胞因子并且通常在炎症区域活跃。先前的研究和我们自己的数据表明IL22信号传导通过与自噬相关的机制减少AP期间组织损伤。 IL22结合蛋白（IL22BP），可溶性中和受体，抑制IL22活性和维持稳态的功能。直到最近才发现它因视黄酸刺激而从树突细胞（DC）释放，并与IL22结合很高亲和力。使用胆管蛋白酶类似素的小鼠诱导AP的诱导导致IL22bp显着下降，表明它可以作为对组织损伤的适应性反应，从而增强了保护性IL22信号。更远支持这一点明显减少了缺乏IL22BP的转基因小鼠的胰腺损伤葡萄蛋白的剂量。该提案的目的是提高我们对IL22信号如何调节的理解 AP通过IL22bp的表达变化。这很重要，正如我们以前证明的那样 IL22的持续过表达与胰腺中的恶性转化有关。我们的中心假设AP中的组织损伤导致IL22BP的自适应降低，这是由于RA的变化而导致的代谢。恢复后IL22bp表达的返回导致IL22信号的稳态抑制。我们将使用来自人类AP队列的转基因小鼠模型和血清样品检验该假设。具体目标1将确定观察到的减少组织损伤的机制由IL22BP - / - 小鼠受到AP的影响。我们将探索IL22信号的变化，特别是与自噬有关并增强与再生有关的基因。基于最初产生酶的关键RA的初步数据， ALDH1A1在AP中明显降低，具体AIM 2将进一步表征视黄酸代谢受伤和恢复期间的胰腺。这将包括使用药理测量来抑制的体内研究 RA代谢，目的是进一步降低IL22BP的生产。特定的目标3将探索串扰在腺泡和免疫细胞之间以及RA在DC生产中的自分泌和旁分泌信号的作用 IL22bp。 RA受体阻滞的使用将作为临床相关的方法探索，以进一步降低 AP期间IL22bp的自适应降低，增强组织恢复并防止进展到严重的AP。