Alternative Macrophage Activation Limits Immunopathology

描述(由申请人提供)：替代巨噬细胞激活限制免疫病理学巨噬细胞(MF)形成一个异质的单核吞噬细胞群体，对器官内稳态、宿主防御和免疫调节是必要的。因此，MF亚型在调节脓毒症、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着核心作用。感染不同的细菌和病毒会引起经典激活的巨噬细胞(CAMF)，它们会产生促炎细胞因子(例如，肿瘤坏死因子、白介素12、白介素23)和一氧化氮(NO)，共同驱动强大的抗微生物功能。相反，过敏反应和蠕虫感染通过暴露于IL-4和/或IL-13刺激交替激活的巨噬细胞(AAMF)的分化，从而促进过敏性疾病和蠕虫破坏。AAMF选择性地表达精氨酸酶(亚型I和II)，将L精氨酸代谢为多胺和脯氨酸，提示AAMF在创面愈合反应和TH2免疫效应细胞中调节细胞增殖和纤维化。曼氏血吸虫是一种主要的人类病原体，影响全球108人，导致多个器官系统的纤维性肉芽肿性炎症。血吸虫的发病机制在人类和小鼠中非常相似，都需要TH2反应才能在感染的急性阶段存活。我们已经生成了几个遗传模型，这些模型有助于仔细机械地剖析TH2相关基因表达的细胞谱系特定重要性。值得注意的是，我们已经证明了IL-4/IL-13驱动的MF活性可以预防小鼠血吸虫病的致死性免疫病理。我们现在有证据表明，精氨酸酶本身负责阻止IL-12/23p40的诱导，驱动胶原的产生，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对于预防感染曼氏血吸虫的小鼠的致命性免疫病理是必要的和充分的；(2)这种保护的机制依赖于精氨酸酶的产生。我们将使用我们的遗传模型在以下目标中解决这些假设：目标1将测试AAMF产生的精氨酸酶I和/或II可防止曼氏血吸虫感染小鼠发生致命性免疫病理的假设；目标2将测试Mf IL-4R1表达对于宿主在血吸虫病期间抵御致死性免疫病理是必要且充分的假设；目标3将测试由CAMF驱动曼氏血吸虫感染小鼠致死性炎症的假设。这些假说具有广泛的意义，超出了在蠕虫感染期间MF的功能，因为MF是一系列慢性人类炎症性疾病的基本组成部分。对MF效应器功能的分子调控有了更深入的了解，应该能够设计出针对此类炎症性疾病的新的治疗方法。巨噬细胞是一种异质的免疫细胞群，在决定许多疾病的预后方面发挥着核心作用，包括感染(如脓毒症)、自身炎症性疾病(如动脉粥样硬化)、过敏性疾病(如哮喘)和癌症。这项建议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对于分化特定的功能群体的MF(或激活的巨噬细胞)是必要的和充分的，通过产生L精氨酸代谢的一种称为精氨酸酶的特定酶来抑制致命性免疫病理。在分子水平上更深入地了解巨噬细胞效应器的功能，应该可以设计出新的治疗方法来治疗由MF控制表达的无数疾病。

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.