Regulation of Inflammatory Signaling during the Innate Immune Response

描述（由申请方提供）：巨噬细胞分布于全身，在全身可检测病原体，随后通过产生炎症介质提醒免疫系统存在感染。炎症介质对于病原体控制至关重要，但如果过度产生，可导致炎性疾病。我的长期目标是了解感染期间巨噬细胞对炎症介质产生的调节。我已经确定了一种新型的负调节炎症反应的病原体通过TREM-2/DAP 12受体复合物。本提案的具体目的是寻求确定TREM-2和DAP 12在体内和体外抑制巨噬细胞中炎症信号传导的机制。具体目标是：1.确定TREM-2和DAP 12抑制巨噬细胞中炎症反应的配体需求。我将检验这样的假设，即通过DAP 12的低亲合力信号导致炎症反应的抑制，而高亲合力信号导致炎症反应的激活。2.确定TREM-2和DAP 12抑制巨噬细胞中炎症信号传导的机制。这些实验将定义DAP 12信号传导如何导致ERK磷酸化和活化的抑制，从而抑制巨噬细胞中的炎性细胞因子产生。3.为了确定为什么DAP 12缺陷小鼠在体内具有增强的先天免疫应答。我将确定在DAP 12缺陷小鼠中增加对单核细胞增生李斯特菌感染的先天反应的机制。我还将研究哪些髓样细胞群被DAP 12信号抑制，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对感染性病原体的早期先天免疫反应提供新的见解。这是在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中具有重要意义的主题，所述病原体包括单核细胞增生李斯特菌（Listeria monocytogenes），其是本提案中提出的MIA类别B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.