Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.
Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis.
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DOI：
10.1242/dmm.020362
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Segal AW
中科院分区：
文献类型：
--
作者：
Chew TS;O'Shea NR;Sewell GW;Oehlers SH;Mulvey CM;Crosier PS;Godovac-Zimmermann J;Bloom SL;Smith AM;Segal AW
克罗恩病（CD）与急性炎症部位的中性粒细胞募集和细菌清除延迟有关，这是由于巨噬细胞分泌促炎细胞因子受损所致。为了研究受损的细胞因子分泌并证实我们先前的发现，我们在巨噬细胞中进行了转录组学分析，并确定了一个自噬受体视神经磷酸酶（OPTN）表达低的CD患者亚组。然后，我们阐明了OPTN缺乏在以下方面的作用：巨噬细胞细胞因子分泌;细菌驱动的结肠炎和腹膜炎的小鼠模型;以及斑马鱼沙门氏菌感染。用热灭活的大肠杆菌刺激的OPTN缺陷型骨髓源性巨噬细胞（BMDM）分泌较少的促炎性TNFα和IL 6细胞因子，尽管基因转录相似，但其在溶酶体和自噬抑制剂的作用下正常化，表明在不存在OPTN的情况下，TNFα通过巴非霉素A依赖性途径错误转运至溶酶体。OPTN缺陷小鼠对柠檬酸杆菌结肠炎和大肠杆菌更敏感。大肠杆菌腹膜炎，并显示血清中促炎性TNFα水平降低，中性粒细胞募集到急性炎症部位减少，死亡率高于野生型小鼠。Optn基因敲低的斑马鱼感染沙门氏菌后死亡率也更高。OPTN在急性炎症和中性粒细胞募集中发挥作用，可能通过缺陷的巨噬细胞促炎细胞因子分泌，这表明人体中OPTN表达减少可能会增加发生CD的风险。总结：视神经磷酸酶在急性炎症、促炎性细胞因子分泌和中性粒细胞募集中起作用，这表明人类视神经磷酸酶表达减少可能增加发生克罗恩病的风险。
Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFα and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFα is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFα in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD. Summary: Optineurin plays a role in acute inflammation, proinflammatory cytokine secretion and neutrophil recruitment, which suggests that diminished optineurin expression in humans might increase the risk of developing Crohn's disease.