Regulation of Inflammatory Signaling during the Innate Immune Response

描述（由申请人提供）：巨噬细胞分布在全身各处，它们可以检测病原体，并随后通过产生炎症介质提醒免疫系统感染的存在。炎症介质是控制病原体的关键，但如果产生过多，可导致炎症性疾病。我的长期目标是了解巨噬细胞在感染过程中产生炎症介质的调控。我已经确定了一种新型的通过TREM-2/DAP12受体复合物对病原体的炎症反应进行负调控。本提案的具体目的是试图在体内和体外确定TREM-2和DAP12抑制巨噬细胞炎症信号传导的机制。具体目标是：1。确定TREM-2和DAP12抑制巨噬细胞炎症反应的配体需求。我将验证通过DAP12的低贪婪信号导致炎症反应抑制，而高贪婪信号导致炎症反应激活的假设。2. 探讨TREM-2和DAP12抑制巨噬细胞炎症信号传导的机制。这些实验将确定DAP12信号如何抑制ERK磷酸化和激活，从而抑制巨噬细胞中炎症细胞因子的产生。3. 确定dap12缺陷小鼠体内先天免疫反应增强的原因。我将确定DAP12缺陷小鼠对单核细胞增生李斯特菌感染的先天反应增加的机制。我还将研究DAP12信号对髓细胞群的抑制作用，以及这是否与TREM-2和TREM-2配体表达相关。这些研究的结果应该为如何控制感染性病原体的早期先天免疫反应提供新的见解。这对于开发预防感染的疫苗和治疗与生物防御相关的病原体感染的免疫调节药物具有重要意义，包括单核细胞增生李斯特菌，这是本提案中讨论的Ml AID B类优先病原体。

DESCRIPTION (provided by applicant): Macrophages are distributed throughout the body where they are poised to detect pathogens and to subsequently alert the immune system to the presence of infection through the production of inflammatory mediators. Inflammatory mediators are critical for pathogen control, but if produced excessively, can result in inflammatory diseases. My long-term goal is to understand the regulation of the production of inflammatory mediators by macrophages during infection. I have identified a novel type of negative regulation of the inflammatory response to pathogens through the TREM-2/DAP12 receptor complex. The specific aims of this proposal seek to define the mechanism of TREM-2 and DAP12 inhibition of inflammatory signaling in macrophages both in vivo and in vitro. The specific aims are: 1. To determine the ligand requirements for TREM-2 and DAP12 inhibition of inflammatory responses in macrophages. I will test the hypothesis that low avidity signals through DAP12 result in inhibition of inflammatory responses, whereas high avidity signals result in activation of inflammatory responses. 2. To determine the mechanism by which TREM-2 and DAP12 inhibit inflammatory signaling in macrophages. These experiments will define how DAP12 signaling results in inhibition of ERK phosphorylation and activation leading to dampening of inflammatory cytokine production in macrophages. 3. To determine why DAP12-deficient mice have enhanced innate immune responses in vivo. I will determine the mechanism for the increased innate response to Listeria monocytogenes infection in DAP12- deficient mice. I also will investigate what myeloid populations are inhibited by DAP12 signaling and whether this correlates with TREM-2 and TREM-2 ligand expression. Results from these studies should provide novel insights into how the early innate immune response to infectious pathogens is controlled. This is a topic of significance in the development of vaccines to prevent infection and immunomodulatory drugs to treat infections with pathogens relevant to biodefense, including Listeria monocytogenes, an Ml AID category B priority pathogen addressed in this proposal.