Role of IRAK-M in sepsis-induced immunosuppression

IRAK-M 在脓毒症诱导的免疫抑制中的作用

• 批准号: 7904894
• 负责人: Jane C Deng
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904894
• 关键词: Abdomen; Alveolar; Alveolar Macrophages; Animals; Bacterial Pneumonia; Bone Marrow; CD14 Antigen; CD14 gene; Cause of Death; Cell Line; Cell Wall; Cell physiology; Cells; Clinical; Critical Illness; Data; Development; Effector Cell; Endotoxins; Functional disorder; Generations; Gram-Negative Bacteria; IRAK1 gene; Immune response; Immune system; Immunosuppression; Impairment; In Vitro; Infection; Inflammatory; Inflammatory Response; Knockout Mice; Ligands; Ligation; Lipopolysaccharides; Lung; Mediating; Mediator of activation protein; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; Nitric Oxide; Nosocomial Infections; Organism; Pathway interactions; Patients; Peritonitis; Phagocytosis; Phosphotransferases; Pneumonia; Predisposition; Pseudomonas aeruginosa; Publications; Publishing; Puncture procedure; Receptor Signaling; Research Personnel; Resistance; Risk; Role; Sepsis; Signal Pathway; TLR4 gene; Testing; Time; Toll-like receptors; Transgenic Mice; United States; antimicrobial; cytokine; human IRAK1 protein; human IRAK3 protein; in vivo; macrophage; microbial; monocyte; mortality; pathogen; patient population; programs; receptor; response; septic; therapeutic target; toll-like receptor 4

DESCRIPTION (provided by applicant): Patients who survive sepsis remain highly susceptible to subsequent nosocomial infections, particularly bacterial pneumonia. Alveolar macrophages are functionally impaired following sepsis, characterized by diminished inflammatory responses to endotoxin and reduced antimicrobial activity. While monocyte/macrophage deactivation is one of the key features of sepsis-induced immunosuppression, the precise cellular and molecular pathways that mediate this phenomenon during sepsis are unclear. Given the hyporesponsiveness of septic macrophages to endotoxin, one of the potential mechanisms for sepsis-induced macrophage deactivation may involve the Toll-like receptor (TLR)4 signaling pathways. TLRs are critical for host recognition of microbial pathogens and the generation of an inflammatory innate immune response, lnterleukin-1 receptor associated kinase-M (IRAK-M) has been demonstrated to be a negative regulator of several TLRs, including TLR4, which is the receptor for lipopolysaccharide (LPS). The hypothesis to be tested in this proposal is that the sepsis-induced impairment of TLR4 signaling pathways in alveolar macrophages is mediated by IRAK-M. To test this hypothesis, these studies will employ a murine model of polymicrobial peritonitis-induced sepsis [cecal ligation and puncture (CLP) model] in both wildtype and IRAK-M knockout mice. The specific aims of this, proposal are to: 1) assess the time-dependent expression of TLR4, CD14, and IRAK-M in alveolar and pulmonary macrophages following CLP; 2) determine the functional significance of IRAK-M on effector cell function and LPS signaling pathways in endotoxin- and sepsis-deactivated alveolar macrophages in vitro; and 3) determine the contribution of IRAK-M to sepsis-induced impairment of lung bacterial clearance in-vivo. Collectively, these studies will enable us to determine if IRAK-M is a relevant mediator of sepsis-induced macrophage deactivation, thereby identifying a potential therapeutic target to reverse the immuno-suppression that occurs in patients with sepsis.

描述（由申请人提供）： 脓毒症存活的患者仍然非常容易发生随后的医院感染，特别是细菌性肺炎。 脓毒症后肺泡巨噬细胞功能受损，其特征在于对内毒素的炎症反应减弱和抗菌活性降低。 虽然单核细胞/巨噬细胞失活是脓毒症诱导的免疫抑制的关键特征之一，但在脓毒症期间介导这种现象的精确细胞和分子途径尚不清楚。鉴于脓毒症巨噬细胞对内毒素的低反应性，脓毒症诱导的巨噬细胞失活的潜在机制之一可能涉及Toll样受体（TLR）4信号通路。 TLR对于微生物病原体的宿主识别和炎性先天免疫应答的产生至关重要，白细胞介素-1受体相关激酶-M（IRAK-M）已被证明是几种TLR的负调节剂，包括TLR 4，其是脂多糖（LPS）的受体。本提案中待检验的假设是，脓毒症诱导的肺泡巨噬细胞中TLR 4信号通路的损伤是由IRAK-M介导的。 为了检验这一假设，这些研究将在野生型和IRAK-M敲除小鼠中采用多微生物腹膜炎诱导的脓毒症小鼠模型[盲肠结扎穿孔（CLP）模型]。 本发明的具体目的是：1）评估CLP后肺泡和肺巨噬细胞中TLR 4、CD 14和IRAK-M的时间依赖性表达; 2）确定IRAK-M对内毒素和脓毒症灭活的肺泡巨噬细胞中的效应细胞功能和LPS信号通路的功能意义;和3）确定IRAK-M对脓毒症诱导的肺细菌清除的体内损害的贡献。 总的来说，这些研究将使我们能够确定IRAK-M是否是脓毒症诱导的巨噬细胞失活的相关介质，从而确定潜在的治疗靶点，以逆转脓毒症患者中发生的免疫抑制。

项目成果

When host defense goes awry: Modeling sepsis-induced immunosuppression.

• DOI: 10.1016/j.ddmod.2011.09.001
• 发表时间: 2012
• 期刊: Drug discovery today. Disease models

Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis.

• DOI: 10.1186/1755-1536-4-10
• 发表时间: 2011-04-04
• 期刊: Fibrogenesis & tissue repair
• 作者: Palchevskiy V;Hashemi N;Weigt SS;Xue YY;Derhovanessian A;Keane MP;Strieter RM;Fishbein MC;Deng JC;Lynch JP 3rd;Elashoff R;Belperio JA
• 通讯作者: Belperio JA