NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function.
NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function.
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DOI：
10.1371/journal.ppat.1007308
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Jeyaseelan S
中科院分区：
文献类型：
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作者：
Ghimire L;Paudel S;Jin L;Baral P;Cai S;Jeyaseelan S
革兰氏阳性菌，包括金黄色葡萄球菌是美国的地方病，从而导致危及生命的坏死性肺炎。已知中性粒细胞对S.金黄色葡萄球菌感染从肺部和肺外器官。因此，我们研究了在肺S.金黄色葡萄球菌感染。与野生型（WT）小鼠不同，NLRP 6基因敲除（KO）小鼠对肺S。金黄色葡萄球菌感染，如通过其较高的存活率和肺和肺外器官中较低的细菌负荷所证明的。此外，NLRP 6 KO小鼠在感染后显示出增加的中性粒细胞募集，并且当中性粒细胞耗尽时，保护作用丧失。此外，来自KO小鼠的中性粒细胞表现出增强的细胞内细菌杀伤和增加的NADPH氧化酶依赖性ROS产生。有趣的是，我们发现KO小鼠肺中NK细胞介导的IFN-γ产生更高，并且发现用IFN-γ处理增强WT和KO中性粒细胞的杀菌能力。NLRP 6 KO小鼠在感染后还显示肺中的焦亡和坏死性凋亡减少。阻断WT小鼠的细胞凋亡和坏死性凋亡导致存活率增加，肺部细菌负荷减少，细胞因子产生减弱。总之，这些新的发现表明，NLRP 6通过调节中性粒细胞流入和功能，在肺部革兰氏阳性细菌感染期间充当嗜中性粒细胞介导的宿主防御的负调节剂。这些结果还表明，阻断NLRP 6以增加嗜酸性粒细胞相关细菌的清除应被视为治疗S.金黄色肺炎包括金黄色葡萄球菌在内的革兰氏阳性菌仍然是全球急性肺炎的主要原因。由于多重耐药菌株的出现，治疗S。金黄色葡萄球菌肺炎是必要的。为此，有可能利用宿主防御来根除感染，而不是直接针对细菌。中性粒细胞是一种重要的先天性免疫细胞类型，是抵抗细菌性肺部感染的第一道防线。NLRP 6是最近发现的Nod样受体家族成员。尽管如此，NLRP 6在急性S.金黄色葡萄球菌肺炎仍然难以捉摸。我们发现NLRP 6基因缺陷/敲除（KO）小鼠在急性S.金黄色肺炎此外，与对照组相比，NLRP 6 KO小鼠的中性粒细胞显示出增强的杀菌能力。类似地，NLRP 6 KO小鼠通过感染后的焦亡和坏死凋亡表现出减少的细胞死亡。在WT小鼠中阻断这些细胞死亡机制导致感染后肺中存活率增加和细菌负荷降低。因此，我们的研究为NLRP 6介导的新机制提供了新的见解，NLRP 6在革兰氏阳性肺炎期间作为嗜中性粒细胞介导的宿主防御的负调节剂。
Gram-positive bacteria, including Staphylococcus aureus are endemic in the U.S., which cause life-threatening necrotizing pneumonia. Neutrophils are known to be critical for clearance of S. aureus infection from the lungs and extrapulmonary organs. Therefore, we investigated whether the NLRP6 inflammasome regulates neutrophil-dependent host immunity during pulmonary S. aureus infection. Unlike their wild-type (WT) counterparts, NLRP6 knockout (KO) mice were protected against pulmonary S. aureus infection as evidenced by their higher survival rate and lower bacterial burden in the lungs and extrapulmonary organs. In addition, NLRP6 KO mice displayed increased neutrophil recruitment following infection, and when neutrophils were depleted the protective effect was lost. Furthermore, neutrophils from the KO mice demonstrated enhanced intracellular bacterial killing and increased NADPH oxidase-dependent ROS production. Intriguingly, we found higher NK cell-mediated IFN-γ production in KO mouse lungs, and treatment with IFN-γ was found to enhance the bactericidal ability of WT and KO neutrophils. The NLRP6 KO mice also displayed decreased pyroptosis and necroptosis in the lungs following infection. Blocking of pyroptosis and necroptosis in WT mice resulted in increased survival, reduced bacterial burden in the lungs, and attenuated cytokine production. Taken together, these novel findings show that NLRP6 serves as a negative regulator of neutrophil-mediated host defense during Gram-positive bacterial infection in the lungs through regulating both neutrophil influx and function. These results also suggest that blocking NLRP6 to augment neutrophil-associated bacterial clearance should be considered as a potential therapeutic intervention strategy for treatment of S. aureus pneumonia. Gram-positive bacteria, including Staphylococcus aureus remain a major cause of acute pneumonia worldwide. Due to emergence of multidrug-resistant strains, alternative strategies for treatment of S. aureus pneumonia are needed. To this end, it may be possible to harness host defenses to eradicate the infection instead of directly targeting the bacteria. Neutrophils are a crucial innate immune cell type and serve as a first line of defense against bacterial lung infection. NLRP6 is a recently identified member of Nod-like receptor family. Nonetheless, the molecular and cellular immunological mechanisms by which the NLRP6 regulates neutrophil-mediated host immunity during acute S. aureus pneumonia remain elusive. We found that NLRP6 gene-deficient/knockout (KO) mice demonstrate increased survival and lower bacterial burden in the lungs along with enhanced neutrophil recruitment during acute S. aureus pneumonia. Moreover, neutrophils from NLRP6 KO mice showed increased bactericidal ability compared to those from controls. Similarly, NLRP6 KO mice demonstrated decreased cell death through pyroptosis and necroptosis following infection. Blocking of these cell death mechanisms in WT mice resulted in increased survival and decreased bacterial burden in the lungs following infection. Therefore, our study provides novel insights into the novel mechanisms mediated by NLRP6, which serves as a negative regulator of neutrophil-mediated host defense during Gram-positive pneumonia.
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DOI：
10.4049/jimmunol.0903843
发表时间：
2010-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cai S;Batra S;Lira SA;Kolls JK;Jeyaseelan S
通讯作者：
Jeyaseelan S
影响因子：
168.9
作者：
DeLeo, Frank R.;Otto, Michael;Kreiswirth, Barry N.;Chambers, Henry F.
通讯作者：
Chambers, Henry F.
中性粒细胞衍生的IL-17A同二聚体诱导IFN-γ诱导肺抗菌防御。
影响因子：
8
作者：
Cai S;Batra S;Langohr I;Iwakura Y;Jeyaseelan S
通讯作者：
Jeyaseelan S
影响因子：
8
作者：
Hefele, Manuela;Stolzer, Iris;Guenther, Claudia
通讯作者：
Guenther, Claudia
影响因子：
24.1
作者：
通讯作者：
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