Hemorrhagic Shock Augments Nlrp3 Inflammasome Activation in the Lung through Impaired Pyrin Induction

被引:43
作者
Xu, Peng [1 ,2 ]
Wen, Zongmei [1 ,2 ]
Shi, Xueyin [2 ]
Li, Yuehua [1 ]
Fan, Liyan [3 ]
Xiang, Meng [1 ,4 ]
Li, Aijun [5 ]
Scott, Melanie J. [1 ]
Xiao, Guozhi [6 ]
Li, Song [7 ]
Billiar, Timothy R. [1 ,8 ]
Wilson, Mark A. [1 ,9 ]
Fan, Jie [1 ,8 ,9 ]
机构
[1] Univ Pittsburgh, Dept Surg, Sch Med, Pittsburgh, PA 15213 USA
[2] Second Mil Med Univ, Changzheng Hosp, Dept Anesthesiol, Shanghai 200003, Peoples R China
[3] Univ Pittsburgh, Sch Arts & Sci, Pittsburgh, PA 15213 USA
[4] Fudan Univ, Dept Physiol & Pathophysiol, Shanghai Med Coll, Shanghai 200032, Peoples R China
[5] Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Shanghai 200003, Peoples R China
[6] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA
[7] Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA
[8] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA
[9] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA
基金
美国国家卫生研究院;
关键词
FAMILIAL MEDITERRANEAN FEVER; RESPIRATORY-DISTRESS-SYNDROME; MULTIPLE ORGAN FAILURE; SEVERE BLUNT TRAUMA; PULMONARY INFLAMMATION; GENE-EXPRESSION; INTERLEUKIN-10; CYTOKINE; INJURY; MEDIATORS;
D O I
10.4049/jimmunol.1203182
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
071005 [微生物学]; 100108 [医学免疫学];
摘要
Hemorrhagic shock (HS) promotes the development of systemic inflammatory response syndrome and organ injury by activating and priming the innate immune system for an exaggerated inflammatory response through, as of yet, unclear mechanisms. IL-1 beta also plays an important role in the development of post-HS systemic inflammatory response syndrome and active IL-1 beta production is tightly controlled by the inflammasome. Pyrin, a protein of 781 aa with pyrin domain at the N-terminal, negatively regulates inflammasome activation through interaction with nucleotide-binding oligomerization domain-like receptor protein (NLRP). Expression of pyrin can be induced by LPS and cytokines, and IL-10 is a known potent inducer of pyrin expression in macrophages. In the current study, we tested the hypothesis that HS downregulates IL-10 and therefore decreases pyrin expression to promote inflammasome activation and subsequent IL-1 beta processing and secretion in the lungs. Our results show that LPS, while activating Nlrp3 inflammasome in the lungs, also induced pyrin expression, which in turn suppressed inflammasome activation. More importantly, LPS-mediated upregulation of IL-10 enhanced pyrin expression, which serves, particularly in later phases, as a potent negative-feedback mechanism regulating inflammasome activation. However, HS-mediated suppression of IL-10 expression in alveolar macrophages attenuated the upregulation of pyrin in alveolar macrophages and lung endothelial cells and thereby significantly enhanced inflammasome activation and IL-1 beta secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative-feedback regulation of Nlrp3 inflammasome to enhance IL-1 beta secretion in response to subsequent LPS challenge and so primes for inflammation.
引用
收藏
页码:5247 / 5255
页数:9
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