{"doi":"10.4049/jimmunol.2100855","title":"Glycolipid Metabolite β-Glucosylceramide Is a Neutrophil Extracellular Trap–Inducing Ligand of Mincle Released during Bacterial Infection and Inflammation","abstract":"Abstract Neutrophil extracellular traps (NETs) are implicated in host defense and inflammatory pathologies alike. A wide range of pathogen- and host-derived factors are known to induce NETs, yet the knowledge about specific receptor–ligand interactions in this response is limited. We previously reported that macrophage-inducible C-type lectin (Mincle) regulates NET formation. In this article, we identify glycosphingolipid β-glucosylceramide (β-GlcCer) as a specific NET-inducing ligand of Mincle. We found that purified β-GlcCer induced NETs in mouse primary neutrophils in vitro and in vivo, and this effect was abrogated in Mincle deficiency. Cell-free β-GlcCer accumulated in the lungs of pneumonic mice, which correlated with pulmonary NET formation in wild-type, but not in Mincle−/−, mice infected intranasally with Klebsiella pneumoniae. Although leukocyte infiltration by β-GlcCer administration in vivo did not require Mincle, NETs induced by this sphingolipid were important for bacterial clearance during Klebsiella infection. Mechanistically, β-GlcCer did not activate reactive oxygen species formation in neutrophils but required autophagy and glycolysis for NET formation, because ATG4 inhibitor NSC185058, as well as glycolysis inhibitor 2-deoxy-d-glucose, abrogated β-GlcCer–induced NETs. Forced autophagy activation by tamoxifen could overcome the inhibitory effect of glycolysis blockage on β-GlcCer–mediated NET formation, suggesting that autophagy activation is sufficient to induce NETs in response to this metabolite in the absence of glycolysis. Finally, β-GlcCer accumulated in the plasma of patients with systemic inflammatory response syndrome, and its levels correlated with the extent of systemic NET formation in these patients. Overall, our results posit β-GlcCer as a potent NET-inducing ligand of Mincle with diagnostic and therapeutic potential in inflammatory disease settings.","journal":"The Journal of Immunology","year":2022,"id":272898,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":660637,"name":"Arun Chauhan","orcid":"0000-0003-3005-1311","position":1,"is_corresponding":false},{"id":520309,"name":"Pooja Chauhan","orcid":null,"position":2,"is_corresponding":false},{"id":940434,"name":"Dustin L. Evans","orcid":null,"position":3,"is_corresponding":false},{"id":939832,"name":"Randolph E. Szlabick","orcid":"0000-0003-3103-5786","position":4,"is_corresponding":false},{"id":939833,"name":"Mary O. Aaland","orcid":"0000-0001-5818-0276","position":5,"is_corresponding":false},{"id":275821,"name":"Bibhuti B. Mishra","orcid":"0000-0002-7203-1653","position":6,"is_corresponding":false},{"id":713223,"name":"Jyotika Sharma","orcid":"0000-0003-0885-0555","position":7,"is_corresponding":false},{"id":771337,"name":"Atul Sharma","orcid":"0000-0002-0189-1920","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"35768151","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":[]}