Role of the M1 macrophage response in the progression of chronic kidney disease

M1巨噬细胞反应在慢性肾病进展中的作用

• 批准号: 8413388
• 负责人: Steven D Crowley
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413388
• 关键词: Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Chronic Kidney Failure; Coculture Techniques; Coupled; Cytokine Signaling; Dialysis procedure; Disease model; Exposure to; Fibrosis; Hypertension; Immune response; In Vitro; Infiltration; Inflammatory; Injury; Interferon Type II; Interferons; Interleukin-1; Interleukin-1 Receptors; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Lymphocyte Subset; Measures; Mediating; Modality; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Receptor, Angiotensin, Type 1; Renal Replacement Therapy; Role; Shapes; Signal Pathway; Stimulus; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Tissues; Tubular formation; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ureteral obstruction; Veterans; cell injury; cytokine; effective therapy; in vivo; kidney cell; macrophage; mortality; normotensive; prevent; receptor; response; response to injury; tissue repair

DESCRIPTION (provided by applicant): Systemic immune responses play an increasingly recognized role in the pathogenesis of chronic kidney disease (CKD). Macrophages help to shape immune responses by differentiating into 2 functional phenotypes: M1 or M2 cells. M1 macrophages secrete pro-inflammatory cytokines and mediate tissue injury whereas M2 macrophages secrete anti-inflammatory cytokines and aid in tissue repair. Consistent with a role for M1 responses in mediating kidney damage, our preliminary studies using CKD models have revealed impressive infiltration of macrophages into the kidney coupled with enhanced renal expression of the M1 effector cytokines Interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a). We therefore hypothesize that M1 macrophages contribute to the progression of CKD through the actions of IL-1 and TNF-a. Mice doubly deficient for the IL-1 receptor (IL-1R) and TNF-receptor 1 (TNFR1) are unable to mount an M1 immune response (M1 KO). Accordingly, to directly test the contribution of the M1 response to CKD, we will measure parameters of kidney injury and fibrosis in M1 KO mice and controls following angiotensin II (Ang II)- dependent hypertension and unilateral ureteral obstruction (UUO). Potential regulators of M1/M2 macrophage differentiation include T lymphocyte subpopulations and type 1 angiotensin (AT1) receptors on macrophages. In this regard, pro-inflammatory Th1 T cells secrete IFN-g, driving macrophages toward the M1 phenotype, whereas in our preliminary studies activation of AT1 receptors directly on macrophages limits the expression of pro-inflammatory M1 cytokines both in the macrophage and the kidney and ameliorates renal damage. We therefore posit that in the setting of CKD, M1 macrophage responses are amplified by actions of Th1 cells but are inhibited by the activation of AT1 receptors on macrophages. We have already found that mice lacking Th1 responses (Tbet KO) have a blunted kidney injury response and muted renal expression of M1 cytokines in the setting of hypertension. Therefore, to determine the impact of Th1 T cells on M1 macrophage responses during renal fibrosis, we will examine kidney damage and M1/M2 macrophage differentiation in Tbet KO mice and controls following UUO. To examine the role of the macrophage AT1 receptor in limiting kidney damage mediated by M1 macrophages, we will further assess UUO- and hypertension-induced kidney injury and M1/M2 differentiation of macrophages in mice lacking the macrophage AT1 receptor (Macro KO) and controls. To define in vitro the mechanisms through which the macrophage AT1 receptor limits renal cell injury, we will co-culture wild-type and Macro KO macrophages with M1 KO, IL-1R KO, TNFR1 KO renal tubular cells and controls and then examine parameters of renal cell injury. We submit that activation of the AT1 receptor on macrophages will blunt the M1 macrophage response and in turn modify M1 cytokine signaling pathways to protect the kidney upon exposure to injurious stimuli. Examining these pathways should lead to more effective strategies for preventing progressive CKD.

描述(由申请人提供)： 系统免疫反应在慢性肾脏病(CKD)的发病机制中发挥着越来越重要的作用。巨噬细胞通过分化成两种功能表型来帮助形成免疫反应：M1或M2细胞。M1巨噬细胞分泌促炎细胞因子并介导组织损伤，而M2巨噬细胞分泌抗炎细胞因子并协助组织修复。与M1反应在介导肾脏损害中的作用一致，我们使用CKD模型进行的初步研究显示，巨噬细胞在肾脏中的渗透令人印象深刻，同时M1效应细胞因子白介素1(IL-1)和肿瘤坏死因子-a(TNF-a)的肾脏表达增加。因此，我们假设M1巨噬细胞通过IL-1和TNF-a的作用参与了CKD的进展。白介素1受体(IL-1R)和肿瘤坏死因子受体1(TNFR1)双重缺陷的小鼠无法产生M1免疫反应(M1KO)。因此，为了直接测试M1反应对CKD的贡献，我们将测量M1KO小鼠和对照组在血管紧张素II(Ang II)依赖型高血压和单侧输尿管梗阻(UUO)后肾脏损伤和纤维化的参数。M_1/M_2巨噬细胞分化的潜在调节因子包括T淋巴细胞亚群和巨噬细胞上的1型血管紧张素(AT1)受体。在这方面，促炎症的Th1T细胞分泌干扰素-g，驱动巨噬细胞向M1表型转变，而在我们的初步研究中，直接激活巨噬细胞上的AT1受体限制了促炎症的M1细胞因子在巨噬细胞和肾脏中的表达，并改善了肾脏损伤。因此，我们推测在CKD的背景下，M1巨噬细胞的反应被Th1细胞的作用放大，但被巨噬细胞上的AT1受体激活而抑制。我们已经发现，缺乏Th1反应的小鼠(Tbet KO)在高血压的背景下肾脏损伤反应迟钝，肾脏M1细胞因子的表达减弱。因此，为了确定Th1T细胞在肾纤维化过程中对M1巨噬细胞反应的影响，我们将检测Tbet KO小鼠和UUO后对照组的肾脏损伤和M1/M2巨噬细胞分化。为了研究巨噬细胞AT1受体在限制M1巨噬细胞介导的肾脏损伤中的作用，我们将进一步评估UUO和高血压诱导的肾脏损伤以及缺乏巨噬细胞AT1受体(Macro KO)的小鼠和对照组巨噬细胞M1/M2分化。为了在体外明确巨噬细胞AT1受体限制肾细胞损伤的机制，我们将野生型和巨噬细胞与M1 KO、IL-1R KO、TNFR1 KO肾小管细胞和对照细胞共同培养，然后检测肾细胞损伤的参数。我们认为，巨噬细胞上AT1受体的激活将钝化M1巨噬细胞的反应，进而修改M1细胞因子信号通路，以在暴露于损伤性刺激时保护肾脏。研究这些途径应该会导致更有效的预防进展性慢性肾脏病的策略。