{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:28:20Z","timestamp":1787315300508,"version":"build-2736575974"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Severe COVID-19 is characterized by profound lung immune dysregulation, yet the pathogenic states and regulatory mechanisms of monocyte-derived macrophages (MDMs) remain poorly defined due to substantial phenotypic heterogeneity across studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>\n                      We integrated multiple single-cell RNA sequencing datasets from COVID-19 lung tissues and bronchoalveolar lavage fluid (BALF) samples to systematically characterize macrophage heterogeneity and differentiation dynamics across anatomical compartments. Trajectory inference, transcription factor activity analysis, and m\n                      <jats:sup>6<\/jats:sup>\n                      A-associated regulatory profiling were performed to delineate molecular programs underlying macrophage state transitions. Cross-dataset validation analyses were conducted to assess the conservation and clinical relevance of identified macrophage states. Functional roles of candidate regulators were further investigated through\n                      <jats:italic>ELAVL1<\/jats:italic>\n                      silencing in monocyte-derived macrophages\n                      <jats:italic>in vitro<\/jats:italic>\n                      , while the pathogenic potential of CD63\n                      <jats:sup>hi<\/jats:sup>\n                      macrophages was evaluated using adoptive transfer experiments in an acute lung injury mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We define a conserved CD63\n                      <jats:sup>hi<\/jats:sup>\n                      terminal inflammatory macrophage state markedly expanded in severe COVID-19 lungs. CD63\n                      <jats:sup>hi<\/jats:sup>\n                      macrophages exhibited enhanced inflammatory cytokine expression together with elevated glycolysis- and hypoxia-associated programs, representing a terminal inflammatory differentiation state along the monocyte-to-MDM trajectory. This population was reproducibly detected across independent datasets and preferentially enriched in lung tissues, with strong associations with disease severity and adverse clinical outcomes. Transcriptional analysis identified\n                      <jats:italic>JUND<\/jats:italic>\n                      activity as progressively increased during macrophage differentiation toward the CD63\n                      <jats:sup>hi<\/jats:sup>\n                      state. In parallel,\n                      <jats:italic>ELAVL1<\/jats:italic>\n                      was associated with inflammatory and metabolic reprogramming programs.\n                      <jats:italic>ELAVL1<\/jats:italic>\n                      silencing suppressed pro-inflammatory cytokine expression, attenuated glycolytic and hypoxia-related pathways, and shifted macrophages toward an immune-regulatory phenotype accompanied by reduced\n                      <jats:italic>CD63<\/jats:italic>\n                      expression. Functionally, adoptive transfer of CD63\n                      <jats:sup>hi<\/jats:sup>\n                      macrophages exacerbated lung inflammation\n                      <jats:italic>in vivo<\/jats:italic>\n                      , resulting in increased cytokine production and neutrophil infiltration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In conclusion, our study defines a conserved CD63\n                      <jats:sup>hi<\/jats:sup>\n                      macrophage inflammatory state in severe COVID-19 and reveals its association with metabolic reprogramming, lung immunopathology, and disease severity.\n                      <jats:italic>ELAVL1<\/jats:italic>\n                      emerges as an important RNA regulatory factor associated with inflammatory macrophage remodeling, highlighting the potential of targeting macrophage regulatory networks as a strategy for modulating pathological inflammation in severe viral infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1874567","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:57:11Z","timestamp":1787313431000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD63hi macrophages define a conserved terminal inflammatory state driving lung immunopathology in severe COVID-19"],"prefix":"10.3389","volume":"16","author":[{"given":"Yaoxi","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital of Jiangnan University","place":["Wuxi, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital of Jiangnan University","place":["Wuxi, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital of Jiangnan University","place":["Wuxi, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital of Jiangnan University","place":["Wuxi, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangkang","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Binhai County People\u2019s Hospital, Binhai Clinical College, Yangzhou University Medical College","place":["Yancheng, Jiangsu, China"]},{"name":"College of Biomedicine and Health, Huazhong Agricultural University","place":["Wuhan, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1016\/j.immuni.2022.08.010","article-title":"Biology of lung macrophages in health and disease","volume":"55","author":"Aegerter","year":"2022","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat. 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