Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Endocr J. 2010;57(1):61-72. doi: 10.1507/endocrj.k09e-296. Epub 2009 Oct 23.
Monocytes/macrophages are key mediators of wound repair, tissue remodeling, and inflammation. However, the molecular mechanisms underlying macrophage recruitment to the site of inflammation is not fully understood. Leptin acts directly on the hypothalamus, thereby regulating food intake and energy expenditure. The leptin receptor, a single transmembrane protein that belongs to the gp130 family of cytokine receptor superfamily, is expressed not only in the hypothalamus but in a variety of peripheral tissues, suggesting the role of leptin as a pro-inflammatory adipocytokine in peripheral tissues. Here, we show that deficiency of leptin signaling reduces renal macrophage infiltration after unilateral ureteral obstruction (UUO). Bone marrow transplantation studies using leptin signaling-deficient db/db mice revealed that leptin signaling in bone marrow cells may not play a major role in the UUO-induced renal macrophage infiltration. Interestingly, central leptin administration reverses the otherwise reduced UUO-induced renal macrophage infiltration in leptin-deficient ob/ob mice. This is effectively abolished by central co-administration of SHU9119, a melanocortin-3 receptor/melanocortin-4 receptor antagonist. This study demonstrates that central leptin administration in ob/ ob mice accelerates renal macrophage infiltration through the melanocortin system, thereby suggesting that the central nervous system, which is inherent to integrate information from throughout the organism, is able to control peripheral inflammation.
单核细胞/巨噬细胞是伤口修复、组织重塑和炎症的关键介质。然而，巨噬细胞募集到炎症部位的分子机制尚不完全清楚。瘦素直接作用于下丘脑，从而调节食物摄入和能量消耗。瘦素受体是一种单跨膜蛋白，属于细胞因子受体超家族的 gp130 家族，不仅在下丘脑表达，而且在各种外周组织中表达，这表明瘦素作为一种促炎脂肪细胞因子在周围组织中的作用。在这里，我们表明瘦素信号缺失可减少单侧输尿管梗阻（UUO）后的肾脏巨噬细胞浸润。使用瘦素信号缺陷 db/db 小鼠进行的骨髓移植研究表明，骨髓细胞中的瘦素信号可能在 UUO 诱导的肾脏巨噬细胞浸润中不起主要作用。有趣的是，中枢瘦素给药可逆转瘦素缺乏 ob/ob 小鼠中否则减少的 UUO 诱导的肾脏巨噬细胞浸润。中央共给予 SHU9119（一种黑皮质素 3 受体/黑皮质素 4 受体拮抗剂）可有效消除这种作用。这项研究表明，中枢瘦素给药可通过黑皮质素系统加速 ob/ob 小鼠的肾脏巨噬细胞浸润，从而表明中枢神经系统能够控制外周炎症，它是固有地整合来自整个机体的信息的。
