Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization
Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization
复制标题
信号素6D反向信号传导调控巨噬细胞脂质代谢和抗炎极化
DOI：
10.1038/s41590-018-0108-0
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发表时间：
2018-06-01
影响因子：
30.5
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
--
作者：
Kang, Sujin;Nakanishi, Yoshimitsu;Kumanogoh, Atsushi
巨噬细胞分化为促炎或抗炎状态具有不同的代谢要求，其中雷帕霉素（rapamycin, mTOR）激酶信号传导的机制靶点起着关键作用。然而，目前尚不清楚mTOR如何调节代谢状态以促进这些细胞的极化。本研究表明，mtor -信号蛋白6D (Sema6D)-过氧化物酶体增殖体受体γ (PPAR γ)轴在巨噬细胞极化中起关键作用。mTOR的抑制或Sema6D的缺失阻断了抗炎巨噬细胞的极化，并伴有PPAR γ表达、脂肪酸摄取和脂质代谢重编程的严重损伤。巨噬细胞表达受体Plexin-A4负责sema6d介导的抗炎极化。我们发现与Sema6D细胞质区相关的酪氨酸激酶c-Abl是PPAR γ表达所必需的。此外，Sema6D对肠道常驻CX3CR1（hi）巨噬细胞的产生很重要，并可防止结肠炎的发生。总之，这些发现强调了Sema6D反向信号在巨噬细胞极化、偶联免疫和通过PPAR γ代谢中的重要作用。
Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor gamma (PPAR gamma) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPAR gamma expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPAR gamma expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1(hi) macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPAR gamma.