Tissue protection by IL-22 during murine inflammation: the influence of gender/sex and use in combination therapy

促炎警报素（也称为DAMP或损伤相关分子模式）从垂死细胞的释放是放大与感染/应激驱动的炎症相关的病理过程的关键因素。因此，旨在稳定组织完整性的治疗干预可能被视为治疗急性和慢性炎症的有前途的新策略。白细胞介素（IL）-22是IL-10细胞因子家族的成员，在损伤相关的肠、肺和肝疾病模型中显示出显著的组织保护潜力。在内源性产生的细胞因子的情况下已经观察到这种功能，并且对于治疗性应用的重组IL-22同样明显。抗凋亡和促增殖转录因子信号转导和转录激活因子（STAT）-3的激活被认为是IL-22的组织保护的关键。值得注意的是，IL-22可以应用于啮齿动物模型而没有立即的副作用。这一观察结果可能与IL-22由于其受体链IL-22 RI的选择性表达而主要作用于上皮来源的细胞但明显不作用于白细胞的事实有关。本研究拟从以下几个方面对IL-22的组织保护作用进行深入研究：1.在组织保护性IL-22和可用于治疗的抗炎细胞因子/细胞因子拮抗剂（IL-10、IL-1受体拮抗剂、IL-18结合蛋白、IL-36结合蛋白）之间是否存在协同作用？2.新发现的IL-22诱导蛋白是否具有细胞保护功能？在这里，重点将放在bcl-3和steap 4上，我们最近证明了它们被IL-22上调。3.原型应激源（热/冷、高渗、一氧化氮、缺氧、机械拉伸）是否决定白细胞亚群释放IL-22和/或IL-22对上皮来源细胞的作用？4. I型IFN在体内决定IL-22的功能特性吗？除了在细胞水平上的实验之外，将利用小鼠模型来研究上述问题。具体而言，本研究项目将采用全身免疫活化（病毒模拟物poly（I：C）给药）和急性肝损伤（对乙酰氨基酚诱导的肝损伤）的体内模型。最近，在澳大利亚启动了一项I期临床试验，评估IL-22生物仿制药在健康志愿者中的安全性。本文概述的实验可以进一步理解IL-22的生物学特性和基于组织保护性IL-22的潜在治疗策略。

Release of pro-inflammatory alarmins (also called DAMPs or damage-associated molecular patterns) from dying cells is a crucial factor that amplifies pathological processes associated with infection/stress-driven inflammation. Therapeutic intervention that aims to stabilize tissue integrity may therefore be regarded as promising novel strategy for the treatment of acute and chronic inflammation. Interleukin (IL)-22 is a member of the IL-10 cytokine family displaying a pronounced tissue protective potential in models of damage-associated intestinal, pulmonary, and hepatic diseases. This function has been observed in the context of the endogenously produced cytokine and is likewise apparent for therapeutically applied recombinant IL-22. Activation of the anti-apoptotic and pro-proliferative transcription factor Signal Transducer and Activator of Transcription (STAT)-3 is supposed to be pivotal for tissue protection by IL-22. Notably, IL-22 can be applied in rodent models without immediate adverse effects. This observation is likely related to the fact that IL-22, due to selective expression of its receptor chain IL-22RI, primarily acts on cells of epithelial origin but strikingly not on leukocytes. In this research project the following aspects of tissue protective IL-22 shall be investigated in detail:1. Is there a synergism between tissue protective IL-22 and anti-inflammatory cytokines/cytokine antagonists (IL-10, IL-1 receptor antagonist, IL-18 binding protein, IL-36 binding protein) which can be employed therapeutically?2. Is there a role for newly identified IL-22-inducible proteins that may serve cytoprotective functions? Here, focus will be on bcl-3 and steap4 which we recently demonstrated to be upregulated by IL-22. 3. Do prototypic stressors (heat/cold, hyperosmolarity, nitric oxide, hypoxia, mechanical stretch) determine the release of IL-22 from leukocyte subsets and/or IL-22 action on cells of epithelial origin?4. Do type I IFN determine functional properties of IL-22 in vivo?Besides experiments on the cellular level, murine models will be utilized to investigate aforementioned matters. Specifically, in vivo models of systemic immunoactivation (administration of the viral mimetic poly (I:C)) and acute liver damage (acetaminophen-induced liver damage) will be employed in this research project. Recently, a phase I clinical trial assessing the safety profile of an IL-22 biosimilar in healthy volunteers has been initiated in Australia. Experiments outlined herein may further our understanding of IL-22 biological properties and potential therapeutic strategies based on tissue protective IL-22.