{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:38:30Z","timestamp":1782970710019,"version":"3.54.5"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Although macrophage heterogeneity has been implicated in pathogenesis, the contribution of transitional macrophage states remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single\u2212cell RNA\u2212seq from 93 human lung specimens (44 IPF, 49 controls) and analyzed peripheral blood single\u2212cell datasets (31 IPF, 17 controls). We examined differentiation trajectories and ligand\u2013receptor networks and assessed metabolic programs. Functional relevance was evaluated in a bleomycin mouse model using histology, immunostaining, qRT\u2212PCR, and tissue glutamine quantification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      We identified an\n                      <jats:italic>\n                        S100A8\n                        <jats:sup>+<\/jats:sup>\n                        S100A9\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:italic>\n                      transitional macrophage population bridging\n                      <jats:italic>\n                        FABP4\n                        <jats:sup>+<\/jats:sup>\n                        MME\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:italic>\n                      precursors and\n                      <jats:italic>\n                        SPP1\n                        <jats:sup>+<\/jats:sup>\n                        MMP9\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:italic>\n                      effector macrophages. These cells are associated with fibrogenesis through two interconnected mechanisms: epidermal growth factor (EGF)-mediated signaling to fibroblasts and alveolar epithelial cells, amplifying profibrotic communication; and glutamine metabolic reprogramming, marked by\n                      <jats:italic>GLUL<\/jats:italic>\n                      . In murine bleomycin induced fibrosis, these features emerged early, with elevated\n                      <jats:italic>S100a8, S100a9, Fcna, Timp1<\/jats:italic>\n                      , and coincided with increased lung glutamine at day 14. Peripheral profiling confirmed concordant transcriptional changes in monocytes from IPF patients, supporting translational biomarker potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      <jats:italic>\n                        S100A8\n                        <jats:sup>+<\/jats:sup>\n                        S100A9\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:italic>\n                      macrophages might function as a druggable immune-metabolic hub in IPF. Targeting\n                      <jats:italic>S100A8\/A9, GLUL<\/jats:italic>\n                      \u2212dependent glutamine flux, or EGFR\u2212axis signaling may enable actionable paths for mechanism\u2212based therapy. Furthermore, their peripheral molecular signature may offer a disease-specific biomarker platform for early diagnosis and therapeutic monitoring.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1832940","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:25:45Z","timestamp":1782966345000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["S100A8+S100A9+ transitional macrophages are associated with pulmonary fibrosis progression by integrating immunometabolism and fibrogenic crosstalk"],"prefix":"10.3389","volume":"17","author":[{"given":"Censhan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyue","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"National Health Commission of the People's Republic of China (NHC) Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University\/Hunan Cancer Hospital","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muxu","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"Henan Academy of Innovations in Medical Science","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanxin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"National Health Commission of the People's Republic of China (NHC) Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Li","family":"Xiang","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"National Health Commission of the People's Republic of China (NHC) Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03743-2","article-title":"A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial","volume":"31","author":"Xu","year":"2025","journal-title":"Nat Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/s2213-2600(25)00045-1","article-title":"Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation","volume":"13","author":"Alonso-Gonzalez","year":"2025","journal-title":"Lancet Respir Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.5355","article-title":"Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis","volume":"329","author":"Maher","year":"2023","journal-title":"Jama"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(25)00239-5","article-title":"Taladegib for the treatment of idiopathic pulmonary fibrosis (ENV-IPF-101): a multicentre, randomised, double-blind, placebo-controlled, phase 2a trial","volume":"13","author":"Maher","year":"2025","journal-title":"Lancet Respir Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.05.007","article-title":"Dectin-1 facilitates lung fungal-mediated pulmonary fibrosis","volume":"58","author":"Qiu","year":"2025","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-042320-030240","article-title":"Pathogenic mechanisms underlying idiopathic pulmonary fibrosis","volume":"17","author":"Moss","year":"2022","journal-title":"Annu Rev Pathology: Mech Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/s2213-2600(22)00251-x","article-title":"Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study","volume":"11","author":"Allen","year":"2023","journal-title":"Lancet Respir Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202407661","article-title":"Modulating fibrotic mechanical microenvironment for idiopathic pulmonary fibrosis therapy","volume":"36","author":"Li","year":"2024","journal-title":"Adv Mater"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(17)30433-2","article-title":"Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper","volume":"6","author":"Lynch","year":"2018","journal-title":"Lancet Respir Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.3669","article-title":"Interstitial lung disease","volume":"331","author":"Maher","year":"2024","journal-title":"Jama"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(22)00475-1","article-title":"Usual interstitial pneumonia as a stand-alone diagnostic entity: the case for a paradigm shift","volume":"11","author":"Selman","year":"2023","journal-title":"Lancet Respir Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2503643","article-title":"Nerandomilast in patients with progressive pulmonary fibrosis","volume":"392","author":"Maher","year":"2025","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/s2213-2600(22)00260-0","article-title":"Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study","volume":"11","author":"Solomon","year":"2023","journal-title":"Lancet Respir Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(21)00173-9","article-title":"Pirfenidone in patients with non-IPF progressive fibrotic interstitial lung diseases: expert guidance is urgently needed","volume":"9","author":"Wells","year":"2021","journal-title":"Lancet Respir Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/jci170499","article-title":"Pulmonary inflammation and fibroblast immunoregulation: from bench to bedside","volume":"133","author":"Ghonim","year":"2023","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02327-2","article-title":"An integrated cell atlas of the lung in health and disease","volume":"29","author":"Sikkema","year":"2023","journal-title":"Nat Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1164\/rccm.202004-1132oc","article-title":"Chemokine receptor 2\u2013targeted molecular imaging in pulmonary fibrosis. A clinical trial","volume":"203","author":"Brody","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106286","article-title":"Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7(high) macrophages in pulmonary fibrosis","volume":"182","author":"Wang","year":"2022","journal-title":"Pharmacol Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl5473","article-title":"Spatial transcriptomic characterization of pathologic niches in IPF","volume":"10","author":"Mayr","year":"2024","journal-title":"Sci Adv"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1038\/s41467-025-57024-0","article-title":"TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity","volume":"16","author":"Cui","year":"2025","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba1983","article-title":"Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis","volume":"6","author":"Adams","year":"2020","journal-title":"Sci Adv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23147749","article-title":"miR449 protects airway regeneration by controlling AURKA\/HDAC6-mediated ciliary disassembly","volume":"23","author":"Wildung","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2205360119","article-title":"Microenvironmental sensing by fibroblasts controls macrophage population size","volume":"119","author":"Zhou","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.300","article-title":"Preliminary analyses of scRNA sequencing and immunohistochemistry of children's lung tissues indicate the expression of SARS-CoV-2 entry-related genes may not be the key reason for the milder syndromes of COVID-19 in children","volume":"11","author":"Tao","year":"2021","journal-title":"Clin Transl Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvac139","article-title":"The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single-cell resolution","volume":"119","author":"de Rooij","year":"2023","journal-title":"Cardiovasc Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100140","article-title":"Osteopontin links myeloid activation and disease progression in systemic sclerosis","volume":"1","author":"Gao","year":"2020","journal-title":"Cell Rep Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.143626","article-title":"Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population","volume":"6","author":"DePianto","year":"2021","journal-title":"JCI Insight"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202306-0979oc","article-title":"Single-cell profiling reveals immune aberrations in progressive idiopathic pulmonary fibrosis","volume":"210","author":"Unterman","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00528.2024","article-title":"Convergent and divergent immune aberrations in COVID-19, post-COVID-19-interstitial lung disease, and idiopathic pulmonary fibrosis","volume":"328","author":"Tourki","year":"2025","journal-title":"Am J Physiol Cell Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat Methods"},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s13073-022-01050-w","article-title":"Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response","volume":"14","author":"Zhang","year":"2022","journal-title":"Genome Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtos.2024.09.003","article-title":"Changes in conjunctival mononuclear phagocytes and suppressive activity of regulatory macrophages in desiccation induced dry eye","volume":"34","author":"Alam","year":"2024","journal-title":"Ocul Surf"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf569","article-title":"MEBOCOST maps metabolite-mediated intercellular communications using single-cell RNA-seq","volume":"53","author":"Zheng","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.045","article-title":"Metabolic modeling of single Th17 cells reveals regulators of autoimmunity","volume":"184","author":"Wagner","year":"2021","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08542-2","article-title":"RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition","volume":"640","author":"Fang","year":"2025","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01266-w","article-title":"SLC15A3 plays a crucial role in pulmonary fibrosis by regulating macrophage oxidative stress","volume":"31","author":"Luo","year":"2024","journal-title":"Cell Death Differ"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01288-5","article-title":"Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy","volume":"22","author":"Li","year":"2025","journal-title":"Cell Mol Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02080-x","article-title":"Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis","volume":"57","author":"Vannan","year":"2025","journal-title":"Nat Genet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06017-4","article-title":"A druggable copper-signalling pathway that drives inflammation","volume":"617","author":"Solier","year":"2023","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.009","article-title":"Cytomegalovirus subverts macrophage identity","volume":"184","author":"Baasch","year":"2021","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06299-8","article-title":"SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity","volume":"620","author":"Guo","year":"2023","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00320-2","article-title":"The metabolism of cancer cells during metastasis","volume":"21","author":"Bergers","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01430-3","article-title":"CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions","volume":"24","author":"Liu","year":"2023","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1832940\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:25:48Z","timestamp":1782966348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1832940\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1832940"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1832940","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"article-number":"1832940"}}