{"doi":"10.1016/j.celrep.2020.03.045","title":"NKT Cells Join the Two Step for Inflammasome-Independent IL-1β Release","abstract":"The cytokine interleukin-1β (IL-1β) is critical for antimicrobial defenses; the inflammasome pathway typically controls IL-1β release, but pathogens often evade this pathway. In this issue, Donado et al., 2020Donado C.A. Cao A.B. Simmons D.P. Croker B.A. Brennan P.J. Brenner M.B. A two-cell model for IL-1beta release mediated by death-receptor signaling.Cell Rep. 2020; 31 (this issue, 107466-1–107466-17)Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar describe an alternative, two-cell model, to instruct inflammasome-independent IL-1β release. The cytokine interleukin-1β (IL-1β) is critical for antimicrobial defenses; the inflammasome pathway typically controls IL-1β release, but pathogens often evade this pathway. In this issue, Donado et al., 2020Donado C.A. Cao A.B. Simmons D.P. Croker B.A. Brennan P.J. Brenner M.B. A two-cell model for IL-1beta release mediated by death-receptor signaling.Cell Rep. 2020; 31 (this issue, 107466-1–107466-17)Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar describe an alternative, two-cell model, to instruct inflammasome-independent IL-1β release. Interleukin-1β (IL-1β) is an inflammatory cytokine important in antimicrobial defenses. It causes fever and initiates the recruitment of innate cells to the site of infection. It also instructs the activation of adaptive immunity and differentiation of effector T cells. IL-1β overproduction is linked to several inherited or acquired chronic inflammatory diseases (e.g., cryopyrin-associated periodic syndrome, type 2 diabetes, rheumatoid arthritis, etc.) and is a therapeutic target for many of them (Dinarello, 2011Dinarello C.A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.Blood. 2011; 117: 3720-3732Crossref PubMed Scopus (1356) Google Scholar). IL-1β release is thus tightly controlled in a cell-intrinsic two-step process (Dinarello, 2011Dinarello C.A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.Blood. 2011; 117: 3720-3732Crossref PubMed Scopus (1356) Google Scholar). Step one upregulates the expression of the inactive cytosolic precursor, pro-IL-1β, in response to pathogen-derived ligands (e.g., lipopolysaccharide) or inflammatory cytokines (e.g., tumor necrosis factor). Step two processes pro-IL-1β precursor into the bioactive, secreted form, typically by the enzyme Caspase-1 (Dinarello, 2011Dinarello C.A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.Blood. 2011; 117: 3720-3732Crossref PubMed Scopus (1356) Google Scholar). Caspase-1 is the effector protease in the inflammasome pathway, a multiprotein cytosolic signaling platform activated upon the loss of cellular homeostasis caused by infection or tissue damage (Broz and Dixit, 2016Broz P. Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling.Nat. Rev. Immunol. 2016; 16: 407-420Crossref PubMed Scopus (1242) Google Scholar). Activated Caspase-1 also cleaves a pore forming protein Gasdermin D (GSDMD), which translocates to the plasma membrane, where it forms large pores to cause the death of the compromised cell (Broz and Dixit, 2016Broz P. Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling.Nat. Rev. Immunol. 2016; 16: 407-420Crossref PubMed Scopus (1242) Google Scholar). The classical in vitro studies of the inflammasome biology have focused on these cell-intrinsic molecular events which underpin the inflammasome pathway. They, nonetheless, failed to answer one key question: how is IL-1β released when cell-intrinsic inflammasome activation is absent or is inhibited by pathogens (Shin and Brodsky, 2015Shin S. Brodsky I.E. The inflammasome: Learning from bacterial evasion strategies.Semin. Immunol. 2015; 27: 102-110Crossref PubMed Scopus (37) Google Scholar)? In this issue of Cell Reports, Donado et al., 2020Donado C.A. Cao A.B. Simmons D.P. Croker B.A. Brennan P.J. Brenner M.B. A two-cell model for IL-1beta release mediated by death-recep","journal":"Cell Reports","year":2020,"id":114980,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9444,"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":282038,"name":"Sebastian Joyce","orcid":"0000-0002-3183-1451","position":1,"is_corresponding":false},{"id":539575,"name":"Jelena S. 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