{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:47:00Z","timestamp":1793278020494,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"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>Scar-associated macrophages (SAMs), defined by triggering receptor expressed on myeloid cells 2 (TREM2) and\/or glycoprotein-NMB (GPNMB) expression, have been implicated in lung fibrosis. This study investigated the characteristics and functional roles of SAMs in lung tissues from patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and healthy controls (HCs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SAM-related transcriptional profiles of lung tissues from patients with SSc-ILD and HCs were analyzed using single-cell RNA sequencing (scRNA-seq). Immunofluorescence staining of lung tissues was performed to detect CD68-positive SAMs expressing TREM2 or CCL2. Monocytes from patients with SSc-ILD and HCs were differentiated with granulocyte\u2013macrophage colony-stimulating factor (GM-CSF) or M-CSF. The population of TREM2- and GPNMB-expressing cells was assessed by flow cytometry, and the levels of CCL2 and TGF-\u03b21 in culture supernatants were measured in an ELISA. The fibrotic effects of macrophages on fibroblasts were examined in co-cultures. TREM2 inhibition was used to determine functional relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq revealed the expansion of TREM2 macrophages highly expressing SAM-associated genes in the lower lung lobes of SSc-ILD patients. Immunofluorescence showed increased numbers of CD68\n                      <jats:sup>+<\/jats:sup>\n                      TREM2\n                      <jats:sup>+<\/jats:sup>\n                      and CD68\n                      <jats:sup>+<\/jats:sup>\n                      CCL2\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in SSc-ILD lung tissues compared to HCs. In GM-CSF-, but not M-CSF-induced CD14\n                      <jats:sup>+<\/jats:sup>\n                      CD16\n                      <jats:sup>+<\/jats:sup>\n                      monocyte-derived macrophages from patients with SSc-ILD, the upregulated expression of TREM2, GPNMB, CCL2, and TGF-\u03b21 recapitulated the transcriptional features of SAM. When these macrophages were co-cultured with fibroblasts, the production of collagen, \u03b1-SMA and TGF-\u03b2 was enhanced. By contrast, TREM2 inhibition significantly reduced these responses, as determined at the bulk RNA-seq and protein levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Our study identified a GM-CSF\u2013TREM2\u2013TGF-\u03b21 axis driving monocytes-derived profibrotic macrophage\u2013fibroblast crosstalk in SSc-ILD. It also showed that, in the lungs of SSc-ILD patients, CD14\n                      <jats:sup>+<\/jats:sup>\n                      CD16\n                      <jats:sup>+<\/jats:sup>\n                      monocyte-derived SAMs drive fibrosis through a TREM2-mediated pathway, which may provide new therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1748574","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:11:30Z","timestamp":1780035090000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["CD14+CD16+ monocyte-derived TREM2 macrophages promote lung fibrosis in systemic sclerosis\u2013interstitial lung disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Jee Young","family":"Kim","sequence":"first","affiliation":[{"name":"Cardiovascular Research Institute","place":["Daegu, Republic of 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