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

• 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
• 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

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。 在美国需要住院治疗，导致每年有275,000人住院。虽然很多人 只有轻微的疾病，一些进展到严重的AP，特征是多系统器官衰竭和死亡。完好无损 免疫对于AP的组织保护和康复至关重要，数据表明，支持和抗AP的失衡 炎性细胞因子可能是疾病进展的基础。有证据表明两人之间存在交流 免疫和上皮细胞在胰腺微环境中的作用，但其在AP中的作用仍未被研究。 需要进一步低调，以确定旨在加强器官修复的潜在疗法。白介素22 白介素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 经常活跃在发炎的区域。先前的研究和我们自己的数据表明，IL22信号 通过与自噬相关的机制减少AP期间的组织损伤。可溶性白介素22结合蛋白(IL22BP) 中和受体，抑制IL22的活性，并具有维持体内平衡的功能。只是最近才发现， 它是树突状细胞(DC)在维甲酸刺激下释放出来的，并与IL22结合，具有很高的 亲和力。用缩胆囊素类似物蓝蛋白诱导小鼠急性胰腺炎，可使IL22BP显著下降。 提示它可能作为对组织损伤的适应性反应，增强保护性IL22信号。进一步 支持这一点的是，在缺乏IL22BP的转基因小鼠中，给予类似的 剂量的雨蛙素。这项建议的目标是提高我们对IL22信号是如何在 AP通过改变IL-22BP的表达来实现。这一点很重要，因为我们之前已经证明了 IL-22持续过表达与胰腺恶性转化有关。我们的中央 假设AP的组织损伤导致IL22BP的适应性降低，这是由于RA的变化引起的 新陈代谢。恢复后IL22BP表达的恢复导致IL22信号的动态平衡抑制。 我们将使用转基因小鼠模型和来自人类AP队列的血清样本来验证这一假设。 具体目标1将确定观察到的组织损伤减少的潜在机制 由IL22BP-/-小鼠诱发的AP。我们将探索IL22信号的变化，特别是与自噬相关的变化 以及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中显著降低，特异性靶点2将进一步表征维甲酸在AP中的代谢。 胰腺在损伤和恢复过程中。这将包括体内研究，使用药物措施来抑制 RA合成代谢，目标是进一步减少IL22BP的产生。《特定目标3》将探索相声。 腺泡和免疫细胞之间的关系以及RA的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的适应性降低，促进组织恢复，防止进展为重症AP。