title: Hemorrhagic shock augments Nlrp3 inflammasome activation in the lung through impaired pyrin induction.
abstract: 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-1β also plays an important role in the development of post-HS systemic inflammatory response syndrome and active IL-1β 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-1β 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-1β secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative-feedback regulation of Nlrp3 inflammasome to enhance IL-1β secretion in response to subsequent LPS challenge and so primes for inflammation.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.forename: Zongmei
authors.initials: Z
authors.lastname: Wen
authors.forename: Xueyin
authors.initials: X
authors.lastname: Shi
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.forename: Liyan
authors.initials: L
authors.lastname: Fan
authors.forename: Meng
authors.initials: M
authors.lastname: Xiang
authors.forename: Aijun
authors.initials: A
authors.lastname: Li
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D034622:RNA Interference; D034741:RNA, Small Interfering; D012771:Shock, Hemorrhagic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome; D051197:Toll-Like Receptor 4 / Q000235:genetics; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C000604193:Mefv protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000071198:Pyrin; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10