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：
10543109
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/10543109
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 Cells Epithelium Equilibrium Flow Cytometry Gastroenterologist Gastrointestinal tract structure Genes Goals Histologic Homeostasis Hospitalization Host Defense Human Immune Immune signaling Immunity In Vitro Inflammation Inflammatory Injury Interleukin Suppression Knock-out Knockout Mice Knowledge Malignant - descriptor Measures Mediator Metabolism Methods Mus Natural regeneration Organ Organ failure Pancreas Pancreatic Diseases Pancreatic Injury Pancreatitis Paracrine Communication Physicians Physiology Prevalence Production Protein Secretion Recovery Research Personnel Research Proposals Retinoic Acid Receptor Retinoic Acid-Binding Proteins Role Sampling Scientist Serum Severities Signal Pathway Signal Transduction Sorting Source Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Tretinoin United States acute pancreatitis analog autocrine biobank body system cell injury clinically relevant cohort cost cytokine experience gastrointestinal improved in vivo insight interleukin-22 mouse model necrotic tissue novel organ repair overexpression oxidation paracrine pharmacologic 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) 是一种胰腺炎症性疾病，是最常见的胃肠道疾病需要在美国住院治疗，每年导致 275,000 人住院。虽然很多仅患有轻微疾病，有些进展为严重 AP，其特征是多系统器官衰竭和死亡。完好无损的免疫对于组织保护和 AP 恢复至关重要，数据表明，亲和抗免疫失衡炎症细胞因子可能是疾病进展的基础。有证据表明双方之间存在沟通胰腺微环境中的免疫和上皮细胞，但其在 AP 中的作用仍未得到充分研究和需要进一步低估以确定旨在增强器官修复的潜在疗法。白细胞介素22 (IL22) 已成为胃肠道内宿主防御和组织修复的重要细胞因子并且经常活跃于炎症区域。之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 期间的组织损伤。 IL22结合蛋白（IL22BP），一种可溶性中和受体，抑制 IL22 活性，并具有维持体内平衡的功能。最近才发现，它响应视黄酸刺激而从树突状细胞 (DC) 中释放出来，并以非常高的强度与 IL22 结合亲和力。使用胆囊收缩素类似物雨蛙素诱导小鼠 AP 会导致 IL22BP 显着下降，表明它可能作为对组织损伤的适应性反应，增强保护性 IL22 信号传导。更远支持这一点的是，在给予类似的条件下，缺乏 IL22BP 的转基因小鼠的胰腺损伤显着减少。雨蛙素的剂量。该提案的目的是提高我们对 IL22 信号传导如何在 AP 通过 IL22BP 表达的变化来实现。这很重要，因为我们之前已经证明了 IL22 的持续过度表达与胰腺的恶性转化有关。我们的中央假设 AP 中的组织损伤导致 IL22BP 适应性下降，这是由 RA 变化引起的代谢。恢复后 IL22BP 表达的恢复会导致 IL22 信号传导的稳态抑制。我们将使用转基因小鼠模型和人类 AP 队列的血清样本来检验这一假设。具体目标 1 将确定观察到的组织损伤减少的机制由IL22BP-/-小鼠进行AP。我们将探索 IL22 信号传导的变化，特别是与自噬相关的变化和增强参与再生的基因。根据初步数据，一种关键的 RA 产生酶， ALDH1A1，在 AP 中显着减少，具体目标 2 将进一步表征 A 中的视黄酸代谢受伤和恢复期间的胰腺。这将包括使用药理学措施来抑制的体内研究 RA 合成代谢的目的是进一步减少 IL22BP 的产生。具体目标3将探讨串扰腺泡和免疫细胞之间的关系以及 RA 自分泌和旁分泌信号在 DC 产生中的作用 IL22BP。将探索使用 RA 受体阻断作为一种临床相关方法，以进一步减少 AP 期间 IL22BP 适应性降低，增强组织恢复并防止进展为严重 AP。