{"doi":"10.4049/jimmunol.2000091","title":"Inhibition of Efferocytosis by Extracellular CIRP–Induced Neutrophil Extracellular Traps","abstract":"Abstract Phagocytic clearance of apoptotic cells by the macrophages (efferocytosis) is impaired in sepsis, but its mechanism is poorly understood. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel damage-associated molecular pattern that fuels inflammation. We identify that eCIRP-induced neutrophil extracellular traps (NETs) impair efferocytosis through a novel mechanism. Coculture of macrophages and apoptotic thymocytes in the presence of recombinant murine CIRP (rmCIRP)–induced NETs significantly inhibited efferocytosis. Efferocytosis was significantly inhibited in the presence of rmCIRP-treated wild-type (WT), but not PAD4−/− neutrophils. Efferocytosis in the peritoneal cavity of rmCIRP-injected PAD4−/− mice was higher than WT mice. Milk fat globule–EGF–factor VIII (MFG-E8), an opsonin, increased macrophage efferocytosis, whereas the inhibition of efferocytosis by NETs was not rescued upon addition of MFG-E8, indicating disruption of MFG-E8’s receptor(s) αvβ3 or αvβ5 integrin by the NETs. We identified neutrophil elastase in the NETs significantly inhibited efferocytosis by cleaving macrophage surface integrins αvβ3 and αvβ5. Using a preclinical model of sepsis, we found that CIRP−/− mice exhibited significantly increased rate of efferocytosis in the peritoneal cavity compared with WT mice. We discovered a novel role of eCIRP-induced NETs to inhibit efferocytosis by the neutrophil elastase–dependent decrease of αvβ3/αvβ5 integrins in macrophages. Targeting eCIRP ameliorates sepsis by enhancing efferocytosis.","journal":"The Journal of Immunology","year":2020,"id":93567,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":267009,"name":"Atsushi Murao","orcid":"0000-0001-9801-3923","position":1,"is_corresponding":false},{"id":319476,"name":"Adnan Arif","orcid":null,"position":2,"is_corresponding":false},{"id":318441,"name":"Satoshi Takizawa","orcid":"0000-0002-4317-2158","position":3,"is_corresponding":false},{"id":318440,"name":"Hui Jin","orcid":"0000-0003-0297-3052","position":4,"is_corresponding":false},{"id":246952,"name":"Jianxin Jiang","orcid":"0000-0003-0907-5976","position":5,"is_corresponding":false},{"id":247093,"name":"Monowar Aziz","orcid":"0000-0002-8195-4505","position":6,"is_corresponding":false},{"id":247094,"name":"Ping Wang","orcid":"0000-0002-1557-0394","position":7,"is_corresponding":false},{"id":467232,"name":"Kehong Chen","orcid":"0000-0003-2437-4309","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T22:31:34.149524Z","pmid":"33380498","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":[]}