{"doi":"10.4049/jimmunol.1203182","title":"Hemorrhagic Shock Augments Nlrp3 Inflammasome Activation in the Lung through Impaired Pyrin Induction","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>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.</jats:p>","journal":"The Journal of Immunology","year":2013,"id":600323,"datarank":0.5897738449086489,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":0.0,"self_endowment_contribution":0.5897738449086489,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1217090,"name":"Zongmei Wen","orcid":"0000-0002-0157-6314","position":1,"is_corresponding":false},{"id":886346,"name":"Xueyin Shi","orcid":null,"position":2,"is_corresponding":false},{"id":927591,"name":"Yuehua Li","orcid":"0000-0002-1504-946X","position":3,"is_corresponding":false},{"id":490025,"name":"Liyan Fan","orcid":"0000-0002-1667-7177","position":4,"is_corresponding":false},{"id":1000456,"name":"Meng Xiang","orcid":"0000-0002-3870-5191","position":5,"is_corresponding":false},{"id":1539021,"name":"Aijun Li","orcid":null,"position":6,"is_corresponding":false},{"id":1539022,"name":"Melanie J Scott","orcid":null,"position":7,"is_corresponding":false},{"id":16868,"name":"Guozhi Xiao","orcid":"0000-0002-4269-2450","position":8,"is_corresponding":false},{"id":459057,"name":"Song Li","orcid":"0000-0002-0661-4893","position":9,"is_corresponding":false},{"id":1539023,"name":"Timothy R Billiar","orcid":null,"position":10,"is_corresponding":false},{"id":1539024,"name":"Mark A Wilson","orcid":null,"position":11,"is_corresponding":false},{"id":367445,"name":"Jie Fan","orcid":"0000-0002-0090-2704","position":12,"is_corresponding":false},{"id":1415182,"name":"Peng Xu","orcid":"0000-0002-2673-7161","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Hemorrhagic Shock Augments Nlrp3 Inflammasome Activation in the Lung through Impaired Pyrin Induction","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23585683","pmcid":"PMC3646900","openalex_id":"https://openalex.org/W2168428983","authors":[],"funders":[{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK072230","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"P50 GM053789","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL079669","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM102146","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"P50-GM-53789","title":null},{"funder_name":"NIAMS NIH HHS","grant_id":"R01 AR059647","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01-HL-079669","title":null}],"total_grants":7,"fwci":2.614,"citation_percentile":0.904318,"influential_citations":0,"citation_trend":[{"year":2013,"count":2},{"year":2014,"count":4},{"year":2015,"count":3},{"year":2016,"count":10},{"year":2017,"count":3},{"year":2018,"count":3},{"year":2019,"count":1},{"year":2020,"count":5},{"year":2021,"count":3},{"year":2022,"count":11},{"year":2024,"count":4},{"year":2025,"count":1}],"oa_status":"bronze","license":"https://academic.oup.com/pages/standard-publication-reuse-rights","oa_locations":[{"url":"https://www.jimmunol.org/content/jimmunol/190/10/5247.full.pdf","host_type":"journal"},{"url":"https://www.jimmunol.org/content/jimmunol/190/10/5247.full.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/jimmunol/article-pdf/190/10/5247/61762007/1203182.pdf","host_type":"publisher"},{"url":"https://doi.org/10.4049/jimmunol.1203182","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23585683","host_type":"repository"},{"url":"http://europepmc.org/articles/PMC3646900","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3646900","host_type":"repository"}],"fields_of_study":["Inflammasome and immune disorders","Heme Oxygenase-1 and Carbon Monoxide","interferon and immune responses"],"mesh_terms":["Pyrin","NLR Family, Pyrin Domain-Containing 3 Protein","Animals","Carrier Proteins","Cells, Cultured","Cytoskeletal Proteins","Disease Models, Animal","Inflammation","Lipopolysaccharides","Lung","Male","Mice, Inbred C57BL","Shock, Hemorrhagic","Signal Transduction","Down-Regulation","Up-Regulation","Macrophages, Alveolar","Interleukin-10","Mice, Knockout","Systemic Inflammatory Response Syndrome","RNA Interference","RNA, Small Interfering","Endothelial Cells","Toll-Like Receptor 4","Mice","Interleukin-1beta","Myeloid Differentiation Factor 88","Inflammasomes"],"keywords":["Pyrin domain","Inflammasome","Shock (circulatory)","Medicine","Lung","Hemorrhagic shock","Immunology","Inflammation","Internal medicine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T12:51:06.627305Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}