A novel role for myeloid cell-specific neuropilin 1 in mitigating sepsis
A novel role for myeloid cell-specific neuropilin 1 in mitigating sepsis
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DOI：
10.1096/fj.201601238r
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发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Zou, Ming-Hui
中科院分区：
文献类型：
--
作者：
Dai, Xiaoyan;Okon, Imoh;Zou, Ming-Hui
败血症-通常由宿主对微生物感染的不受控制和放大的全身炎症反应-是一种威胁生命的复杂临床疾病，仍然是重症监护病房感染相关死亡的主要原因。新的证据表明，Nrp1是最初定义的3类信号素和血管内皮生长因子的辅助受体，在免疫系统中发挥重要作用；然而，巨噬细胞Nrp1在宿主免疫防御细菌感染中的功能和调节仍不清楚。为了解决这个问题，我们建立了髓系细胞特异性Nrp1基因敲除(Nrp1)小鼠，并应用了两种严格的脓毒症动物模型：盲肠结扎和穿孔以及内毒素注射。在这里，我们报告了髓系细胞特异性Nrp1缺陷小鼠对盲肠结扎和穿孔以及内毒素诱导的脓毒症的易感性增加，这与显著降低存活率和增加腹膜灌洗液和血清中的促炎细胞因子水平有关。在机制上，内毒素特异性地抑制巨噬细胞中Nrp1的表达，这是通过TLR4、NF-kBp50和-65途径介导的。通过使用分离的初级巨噬细胞，Nrp1的丢失持续导致促炎细胞因子的产生增加，包括iNOS、TNF-α和IL-6。综上所述，这些发现表明了巨噬细胞Nrp1在脓毒症中的新作用。戴锡恩，奥肯，I.，刘振中，吴勇，朱，H.，宋，P.，邹明华.髓系细胞特异性神经毛细蛋白1在减轻脓毒症中的新作用.
Sepsis-typically caused by an uncontrolled and amplified host systemic inflammatory response to microbial infection-is a life-threatening complex clinical disorder and remains a major cause of infection-related deaths in the intensive care unit. Emerging evidence suggests that neuropilin 1 (Nrp1), an originally defined coreceptor for class 3 semaphorins and VEGF, plays important roles in the immune system; however, the function and regulation of macrophage Nrp1 in host immune defense against bacterial infection remain unknown. To address this problem, we generated myeloid cell specific Nrp1-knockout (Nrp1 mice and applied 2 stringent animal models of sepsis: cecal ligation and puncture as well as intraperitoneal injection of LPS. Here, we reported that myeloid cell specific Nrp1-deficient mice exhibited enhanced susceptibility to cecal ligation and puncture and LPS-induced sepsis, which correlated with significantly decreased survival rates and heightened levels of proinflammatory cytokines in both peritoneal lavage and serum. Mechanistically, LPS specifically attenuated the expression of Nrp1 in macrophages, which was mediated by TLR4 NF-KB p50 and-65 pathways. By using isolated primary macrophages, loss of Nrp1 consistently resulted in increased production of proinflammatory cytokines, including iNOS, TNF-alpha, and IL-6. Together, these findings demonstrate a novel role of macrophage Nrp1 in sepsis. Dai, X. Okon, I., Liu, Z., Wu, Y., Zhu, H., Song, P., Zou, M.-H. A novel role for myeloid cell specific neuropilin 1 in mitigating sepsis.