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Technical advances in single-cell RNA sequencing define transcriptome-based granulocyte subsets beyond classical density- and surface marker-based classifications. These approaches reveal substantial heterogeneity in granulocyte differentiation states, activation programs, and tissue adaptation across human diseases. In microscopic polyangiitis, type II interferon (IFN) pathways shape a pathogenic neutrophil activation state, and serum IFN\u03b3 levels at disease onset may serve as a potential biomarker for subsequent relapse. In infectious diseases, including coronavirus disease 2019 (COVID-19) and sepsis, the expansion of immunosuppressive ARG1- and IL1R2-expressing neutrophils is reported in severe disease and may reflect altered immune responses. MMP9-high neutrophils are enriched in cardiovascular disorders and may be linked to thrombosis and ischemic injury. In allergic diseases, spatial and single-cell analyses identify tissue-specific eosinophil states and their interactions with epithelial and macrophage compartments, highlighting context-dependent eosinophil activation within inflamed tissues. Despite emerging evidence for disease-associated granulocyte heterogeneity, whether these populations causally contribute to disease pathophysiology remains largely unclear. Experimentally validated functions and clinically applicable surrogate markers, such as surface markers or circulating proteins, are still needed. This review summarizes recent advances and current limitations in understanding granulocyte heterogeneity across immune-mediated and inflammatory diseases and discusses how integrative single-cell approaches may support the development of clinically relevant biomarkers and targeted therapeutic strategies.<\/jats:p>","DOI":"10.1093\/intimm\/dxag026","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T09:11:41Z","timestamp":1779786701000},"page":"585-593","source":"Crossref","is-referenced-by-count":0,"title":["Granulocyte heterogeneity in immune-mediated and inflammatory diseases: insights from single-cell transcriptomic analyses"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7820-364X","authenticated-orcid":false,"given":"Hiroshi","family":"Shimagami","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-7117","authenticated-orcid":false,"given":"Atsushi","family":"Kumanogoh","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Japan Agency for Medical Research and Development\u2014Core Research for Evolutional Science and Technology (AMED\u2013CREST), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Center for Infectious Diseases for Education and Research (CiDER), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Center for Advanced Modalities and DDS (CAMaD), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6060-1228","authenticated-orcid":false,"given":"Masayuki","family":"Nishide","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]},{"name":"Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, The University of Osaka , Suita, Osaka 565-0871 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"2026100105520786500_dxag026-B1","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1172\/JCI105568","article-title":"In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood","volume":"46","author":"Quie","year":"1967","journal-title":"J Clin Invest"},{"key":"2026100105520786500_dxag026-B2","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1172\/JCI107236","article-title":"Biological defense mechanisms. 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