Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy
Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy
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DOI：
10.1152/ajprenal.00191.2021
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发表时间：
2021-12-01
影响因子：
4.2
通讯作者：
Oshima, Naoki
中科院分区：
文献类型：
--
作者：
Ito, Seigo;Nakashima, Hiroyuki;Oshima, Naoki
糖尿病肾病（DN）的发病机制与巨噬细胞（M phi）向肾脏的募集、肿瘤坏死因子-α（TNF-α）的产生和氧化应激有关。据报道，Toll样受体9（TLR 9）活化参与全身性炎症，并且它在代谢综合征中加重这种状况。因此，我们推测TLR 9在DN的发病机制中起作用。采用流式细胞术分析DN模型（db/db）小鼠肾脏M phi s的两个亚群的分布和TLR 9的表达及功能。给小鼠注射CCR 2拮抗剂INCB 3344 8 wk，观察M phi分布和功能的变化，以及对DN病理的治疗作用。在小鼠肾脏中鉴定了骨髓来源的CD 11b（高）（BM-M phi）和组织驻留的CD 11b（低）M phi s（Res-M phi）。随着DN的进展，BM-M phi数量、TLR 9表达和TNF-α产生显著增加。在Res-M phi s中，活性氧（ROS）的产生和吞噬活性增强。INCB 3344降低白蛋白尿、血清肌酐水平、BM-M phi丰度、TLR 9表达和BM-M phi s产生的TNF-α和Res-M phi s产生的ROS。通过TLR 9和TNF-α产生的BM-M phi活化增加以及Res-M phi s产生的ROS增加均参与DN进展。因此，通过INCB 3344灭活M phi s及其TLR 9表达是DN的潜在治疗策略。新的和值得注意的是，我们将肾巨噬细胞（M phi s）分类为表达高CD 11b的骨髓源性M phi s（BM-M phi s）和表达低CD 11b的组织特异性驻留Mop（Res-M phi s）。在糖尿病肾病（DN）模型小鼠中，BM-M phi s中Toll样受体9（TLR 9）表达和经由TLR 9活化的TNF-α产生以及Res-M phi s中ROS产生增强。此外，CCR 2拮抗剂抑制BM-M phi s的肾脏浸润及其功能和Res-M phi s产生的ROS，同时抑制TLR 9。本研究为DN的治疗提供了新的策略。
The pathogenesis of diabetic nephropathy (DN) is related to macrophage (M phi) recruitment to the kidneys, tumor necrosis factor-alpha (TNF-alpha) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney M phi s in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in M phi distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11b(high) (BM-M phi) and tissue-resident CD11b(low) M phi s (Res-M phi) were identified in the mouse kidneys. As DN progressed, the BM-M phi number, TLR9 expression, and TNF-alpha production increased significantly. In Res-M phi s, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-M phi abundance, TLR9 expression, and TNF-alpha production by BM-M phi s and ROS production by Res-M phi s. Both increased activation of BM-M phi via TLR9 and TNF-alpha production and increased ROS production by Res-M phi s were involved in DN progression. Thus, inactivating M phi s and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN.NEW & NOTEWORTHY We classified kidney macrophages (M phi s) into bone marrow-derived M phi s (BM-M phi s) expressing high CD11b and tissue-specific resident Mop (Res-M phi s) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-alpha production via TLR9 activation in BM-M phi s and ROS production in Res-M phi s were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-M phi s and their function and the ROS production by Res-M phi s, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.