Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
Sci Rep. 2017 Jan 23;7:41106. doi: 10.1038/srep41106.
Sepsis is a systemic inflammatory response to bacterial infection. The therapeutic options for treating sepsis are limited. Impaired neutrophil recruitment into the infection site is directly associated with severe sepsis, but the precise mechanism is unclear. Here, we show that Mincle plays a key role in neutrophil migration and resistance during polymicrobial sepsis. Mincle-deficient mice exhibited lower survival rates in experimental sepsis from cecal ligation and puncture and Escherichia coli-induced peritonitis. Mincle deficiency led to higher serum inflammatory cytokine levels and reduced bacterial clearance and neutrophil recruitment. Transcriptome analyses revealed that trehalose dimycolate, a Mincle ligand, reduced the expression of G protein-coupled receptor kinase 2 (GRK2) in neutrophils. Indeed, GRK2 expression was upregulated, but surface expression of the chemokine receptor CXCR2 was downregulated in blood neutrophils from Mincle-deficient mice with septic injury. Moreover, CXCL2-mediated adhesion, chemotactic responses, and F-actin polymerization were reduced in Mincle-deficient neutrophils. Finally, we found that fewer Mincle-deficient neutrophils infiltrated from the blood circulation into the peritoneal fluid in bacterial septic peritonitis compared with wild-type cells. Thus, our results indicate that Mincle plays an important role in neutrophil infiltration and suggest that Mincle signaling may provide a therapeutic target for treating sepsis.
脓毒症是一种细菌感染引起的全身炎症反应。目前治疗脓毒症的方法有限。中性粒细胞不能向感染部位募集与严重脓毒症直接相关，但确切的机制尚不清楚。在这里，我们发现 Mincle 在多微生物脓毒症中对中性粒细胞迁移和抵抗起着关键作用。在盲肠结扎穿孔和大肠杆菌诱导的腹膜炎实验性脓毒症中，Mincle 缺陷型小鼠的存活率较低。Mincle 缺乏导致血清炎症细胞因子水平升高，细菌清除率和中性粒细胞募集减少。转录组分析显示，甘露糖二酰基脂，一种 Mincle 配体，降低了中性粒细胞中 G 蛋白偶联受体激酶 2（GRK2）的表达。事实上，在脓毒症损伤的 Mincle 缺陷型小鼠的血液中性粒细胞中，GRK2 的表达上调，但趋化因子受体 CXCR2 的表面表达下调。此外，CXCL2 介导的黏附、趋化反应和 F-actin 聚合在 Mincle 缺陷型中性粒细胞中减少。最后，我们发现与野生型细胞相比，在细菌性脓毒症性腹膜炎中，较少的 Mincle 缺陷型中性粒细胞从血液循环渗透到腹腔液中。因此，我们的结果表明 Mincle 在中性粒细胞浸润中起着重要作用，并表明 Mincle 信号可能为治疗脓毒症提供一个治疗靶点。
