Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization.
Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via Gβγ/PKC/ERK1/2 pathway and heterologous receptor desensitization.
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DOI：
10.1038/srep42279
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发表时间：
2017-02-10
影响因子：
4.6
通讯作者：
Zhou N
中科院分区：
文献类型：
--
作者：
Shi Y;Lai X;Ye L;Chen K;Cao Z;Gong W;Jin L;Wang C;Liu M;Liao Y;Wang JM;Zhou N
烟酸受体HCA 2参与控制炎症宿主反应，但机制基础知之甚少。我们以前报道A431上皮细胞中的HCA 2转导Gβγ-蛋白激酶C和Gβγ-金属蛋白酶/EGFR依赖的MAPK/ERK信号级联。在此，我们研究了HCA 2在巨噬细胞介导的炎症中的作用及其潜在机制。我们发现促炎刺激剂LPS、IL-6和IL-1β可上调巨噬细胞HCA 2的表达。烟酸通过破坏F-actin和Gβ蛋白的极化分布，显著抑制巨噬细胞对趋化因子fMLF和CCL 2的趋化作用。烟酸对化学引诱剂诱导的ERK 1/2、JNK和PI 3 K通路的激活显示出选择性的累加效应，但只有MEK抑制剂UO 126减少烟酸介导的巨噬细胞趋化性抑制，而EGF单独激活ERK 1/2并不能抑制fMLF介导的共表达HCA 2和fMLF受体FPR 1的HEK 293 T细胞迁移。此外，烟酸诱导FPR 1的异源脱敏和内化。此外，烟酸通过减少炎症症状将小鼠从脓毒性休克中拯救出来，并且在HCA 2 −/−小鼠中消除了这种效果。这些结果表明，Gβγ/PKC依赖的ERK 1/2激活和异源脱敏的趋化因子受体参与烟酸抑制趋化因子诱导的巨噬细胞迁移。因此，HCA 2在宿主保护免受促炎性损伤中起关键作用。
The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. We previously reported that HCA2 in A431 epithelial cells transduced Gβγ-protein kinase C- and Gβγ-metalloproteinase/EGFR-dependent MAPK/ERK signaling cascades. Here, we investigated the role of HCA2 in macrophage-mediated inflammation and the underlying mechanisms. We found that proinflammatory stimulants LPS, IL-6 and IL-1β up-regulated the expression of HCA2 on macrophages. Niacin significantly inhibited macrophage chemotaxis in response to chemoattractants fMLF and CCL2 by disrupting polarized distribution of F-actin and Gβ protein. Niacin showed a selected additive effect on chemoattractant-induced activation of ERK1/2, JNK and PI3K pathways, but only the MEK inhibitor UO126 reduced niacin-mediated inhibition of macrophage chemotaxis, while activation of ERK1/2 by EGF alone did not inhibit fMLF-mediated migration of HEK293T cells co-expressing HCA2 and fMLF receptor FPR1. In addition, niacin induced heterologous desensitization and internalization of FPR1. Furthermore, niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2−/− mice. These results suggest that Gβγ/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. Thus, HCA2 plays a critical role in host protection against pro-inflammatory insults.