Alternative Macrophage Activation Limits Immunopathology

描述（由申请人提供）：替代巨噬细胞活化限制免疫病理学巨噬细胞（MF）形成器官稳态、宿主防御和免疫调节所需的单核吞噬细胞的异质群体。因此，MF亚型在调节如败血症、动脉粥样硬化和哮喘等多种疾病的发病机制和表达方面发挥核心作用。不同细菌和病毒的感染产生经典活化的巨噬细胞（CAMF），其产生促炎细胞因子（例如，TNF，IL-12，IL-23）和一氧化氮（NO），共同驱动有效的抗微生物功能。相反，过敏反应和蠕虫感染通过暴露于促进过敏性疾病和蠕虫破坏的IL-4和/或IL-13刺激交替激活的巨噬细胞（AAMF）的分化。AAMF选择性地表达精氨酸酶（亚型I和II）以将L-精氨酸代谢成多胺和脯氨酸，暗示AAMF作为伤口愈合反应期间的细胞增殖和纤维化的调节剂和辅助性T细胞2型（TH 2）免疫的效应细胞。曼氏血吸虫是一种主要的人类病原体，在全球范围内影响108人，导致多器官系统的纤维化肉芽肿性炎症。血吸虫病的发病机制在人类和小鼠中非常相似，两者都需要TH 2应答才能在感染的急性期存活。我们已经产生了几个遗传模型，便于仔细的机制解剖的细胞系特异性的重要性TH 2相关的基因表达。值得注意的是，我们已经证明，IL-4/IL-13驱动的MF活性防止小鼠血吸虫病的致命免疫病理学。我们现在有证据表明，胰蛋白酶本身负责阻断IL-12/23 p40诱导，驱动胶原蛋白产生，并限制肝脏和肠道的严重炎症。总之，这些数据有力地支持了我们相互关联的中心假设：（1）AAMF是必要的，足以防止感染曼氏血吸虫的小鼠的致死性免疫病理学;（2）这种保护机制依赖于酶的产生。我们将使用我们的遗传模型来解决这些假设在以下目标：目标1将测试的假设，AAMF生产精氨酸酶I和/或II防止致命的免疫病理学在S。曼氏感染小鼠;目的2将检验MF IL-4 R1表达对于血吸虫病期间宿主针对致死性免疫病理学的保护是必要的和充分的假设;目的3将检验血吸虫病中致死性炎症是必需的和充分的假设。感染曼氏菌的小鼠是由CAMF驱动的。这些假说具有广泛的意义，超越了MF功能在蠕虫感染，因为MF是一个广泛的人类慢性炎症性疾病的基本组成部分。对MF效应子功能的分子调节的更大的机制理解应该允许设计针对此类炎性疾病的新的治疗方法。巨噬细胞（MF）是免疫细胞的异质群体，其在确定许多疾病的结果中起核心作用，包括感染（例如，脓毒症），自身炎性疾病（例如，动脉粥样硬化）、过敏性疾病（例如哮喘）和癌症。本提案将使用小鼠炎症模型来检验我们的假设，即白细胞介素4和13对于MF（交替激活的巨噬细胞[AAMF]）的特定功能群体的分化是必不可少的，这些功能群体通过产生一种称为精氨酸酶的L-精氨酸代谢的特异性酶来抑制致死性免疫病理学是必要的和足够的。在分子水平上对巨噬细胞效应器功能的更深入的机制理解应该允许设计新的治疗方法来治疗其表达受MF控制的无数疾病。

DESCRIPTION (provided by applicant): Alternative macrophage activation limits immunopathology Macrophages (MF) form a heterogeneous population of mononuclear phagocytes necessary for organ homeostasis, host defense, and immunoregulation. As such, MF subtypes play a central role in regulating the pathogenesis and expression of diseases as diverse as sepsis, atherosclerosis and asthma. Infection with diverse bacteria and viruses gives rise to classically activated macrophages (CAMF), which produce pro- inflammatory cytokines (e.g., TNF, IL-12, IL-23) and nitric oxide (NO) that, together, drive potent anti-microbial functions. In contrast, allergic reactions and worm infestation stimulate the differentiation of alternatively activated macrophages (AAMF) via exposure to IL-4 and/or IL-13 that promotes allergic disease and helminth destruction. AAMF selectively express arginases (isoforms I and II) to metabolize L-arginine into polyamines and proline, implicating AAMF as regulators of cellular proliferation and fibrosis during the wound healing response and effector cells of T helper type 2 (TH2) immunity. Schistosoma mansoni is a major human pathogen affecting 108 people worldwide that causes fibrotic granulomatous inflammation in multiple organ systems. Schistosoma pathogenesis is remarkably similar in humans and mice, both of which require TH2 responses for survival during the acute phase of infection. We have generated several genetic models that facilitate careful mechanistic dissection of the cell-lineage specific importance of TH2 associated gene expression. Notably, we have demonstrated that IL-4/IL-13-driven MF activity prevents lethal immunopathology in mouse schistosomiasis. We now have evidence that arginase itself is responsible for blocking IL-12/23p40 induction, driving collagen production, and limiting severe inflammation of liver and intestine. Together, these data strongly support our inter-related central hypotheses: (1) AAMF are necessary and sufficient to prevent lethal immunopathology in mice infected with Schistosoma mansoni; and (2) The mechanism of such protection is dependent on arginase production. We will use our genetic models to address these hypotheses in the following aims: Aim 1 will test the hypothesis that AAMF production of Arginases I and/or II prevents lethal immunopathology in S. mansoni- infected mice; Aim 2 will test the hypothesis that MF IL-4R1 expression is necessary and sufficient for host protection against lethal immunopathology during Schistosomiasis; Aim 3 will test the hypothesis that lethal inflammation in S. mansoni-infected mice is driven by CAMF. These hypotheses have broad implications that go beyond MF function during worm infection because MF are fundamental components of a wide range of chronic human inflammatory diseases. A greater mechanistic understanding of the molecular regulation of MF effector function should allow for the design of novel therapeutic approaches to such inflammatory diseases.Macrophages (MF) are a heterogeneous population of immune cells that play a central role in determining the outcome of many diseases, including infections (e.g., sepsis), autoinflammatory diseases (e.g., atherosclerosis), allergic diseases (e.g. asthma) and cancer. This proposal will use a mouse model of inflammation to test our hypothesis that interleukins 4 and 13 are essential for the differentiation of a specific functional population of MF (alternatively activated macrophages [AAMF]) that are both necessary and sufficient for suppression of lethal immunopathology by producing a specific enzyme of L-arginine metabolism called arginase. A greater mechanistic understanding of macrophage effector function on a molecular level of should allow for the design of novel therapeutic approaches to the myriad diseases whose expression is controlled by MF.