Nod2 and Rip2 contribute to innate immune responses in mouse neutrophils
Nod2 and Rip2 contribute to innate immune responses in mouse neutrophils
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DOI：
10.1111/imm.12307
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发表时间：
2014-10-01
期刊：
影响因子：
6.4
通讯作者：
Park, Jong-Hwan
中科院分区：
文献类型：
--
作者：
Jeong, Yu-Jin;Kang, Min-Jung;Park, Jong-Hwan
Nod-like受体是一个天然免疫受体家族，其将微生物和危险刺激物的胞质感测与免疫应答的激活联系起来。两个Nod样受体家族成员Nod 1和Nod 2识别细菌肽聚糖并通过核因子-κ B（NF-κ B B）和丝裂原活化蛋白激酶（MAPK）激活免疫应答。Nod 1和Nod 2的功能已经在巨噬细胞中进行了大量研究，但这些受体在其他先天免疫细胞中的作用仍不清楚。在这项研究中，我们研究了Nod 1和Nod 2在中性粒细胞天然免疫反应中的功能。小鼠腹腔注射巯基乙酸盐，然后在注射后4小时分离腹膜中性粒细胞。Tri-DAP和胞壁酰二肽（MDP）分别用作Nod 1和Nod 2激动剂。在野生型（WT）中性粒细胞中，MDP可增加细胞因子[白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）]和趋化因子（CXCL 1和CCL 2）的水平，但Tri-DAP未增加。在Nod 2和Rip 2缺陷型中性粒细胞中，MDP导致细胞因子和趋化因子的产生增加。MDP还诱导WT中性粒细胞中NF-κ B和MAPK的活化，但在Nod 2和Rip 2缺陷细胞中不诱导。流式细胞术分析表明，L-选择素脱落诱导MDP在WT中性粒细胞，但不是在Nod 2和Rip 2缺陷细胞。MDP和Toll样受体（TLR）激动剂（Pam（3）CSK（4）和脂多糖）对中性粒细胞中IL-6和CXCL 1的产生产生具有协同作用。此外，Nod 2和TLR 4协同产生IL-6，TNF-α，CXCL 1和CCL 2在中性粒细胞中响应革兰氏阴性菌。我们的研究结果表明，Nod 2-Rip 2轴可能有助于中性粒细胞对细菌感染的先天免疫反应。
Nod-like receptors are a family of innate immune receptors that link cytosolic sensing of microbial and danger stimuli to the activation of immune responses. Two Nod-like receptor family members, Nod1 and Nod2, recognize bacterial peptidoglycan and activate immune responses via nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK). The function of Nod1 and Nod2 has been largely studied in macrophages, but the role of these receptors in other innate immune cells remains unclear. In this study, we examined the function of Nod1 and Nod2 in innate immune responses of neutrophils. Mice were injected intraperitoneally with thioglycollate, and then peritoneal neutrophils were isolated 4 hr after injection. Tri-DAP and muramyl-dipeptide (MDP) were used as Nod1 and Nod2 agonists, respectively. The level of cytokines [interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha)] and chemokines (CXCL1 and CCL2) was increased by MDP, but not Tri-DAP in wild-type (WT) neutrophils. Increased production of cytokines and chemokines with MDP was abolished in Nod2- and Rip2-deficient neutrophils. MDP also induced the activation of NF-kappa B and MAPK in WT neutrophils, but not in Nod2 -and Rip2-deficient cells. Flow cytometry analysis showed that L-selectin shedding was induced by MDP in WT neutrophils, but not in Nod2 -and Rip2-deficient cells. MDP and Toll-like receptor (TLR) agonists (Pam(3)CSK(4) and lipopolysaccharide) exerted synergistic effects on the production of IL-6 and CXCL1 in neutrophils. Moreover, Nod2 and TLR4 cooperated to produce IL-6, TNF-alpha, CXCL1 and CCL2 in neutrophils in response to Gram-negative bacteria. Our findings suggest that the Nod2-Rip2 axis may contribute to the innate immune response of neutrophils against bacterial infection.