TREM2+ lung macrophages and serum soluble TREM2 in anti-MDA5-positive dermatomyositis-associated interstitial lung disease

Objective To characterise TREM2-expressing lung macrophage states in anti-MDA5-positive dermatomyositis (DM)-associated interstitial lung disease (ILD) and to evaluate serum soluble TREM2 (sTREM2) as a biomarker. Methods Public lung scRNA-seq data from a single anti-MDA5+ DM-ILD case and nine healthy donors were integrated. Serum sTREM2 was measured by ELISA in 25 newly diagnosed anti-MDA5+ DM patients and 15 matched healthy controls; 12-month follow-up samples were available for 19. Associations with ILD, laboratory indices and pulmonary function were analyzed. Results Exploratory scRNA-seq analysis suggests TREM2 was enriched in lung macrophages in a single anti-MDA5+ DM-ILD lung sample. Within this sample, TREM2+ macrophages showed higher interferon-response and M2 scores, lower M1 scores, and increased expression of profibrotic genes (SPP1, PLA2G7, FABP5 and PDGFA). In a bleomycin mouse model, TREM2+ Macrophages were significantly increased at day 7 and were surrounded by abundant profibrotic POSTN+CTHRC1+ myofibroblasts at day 21. Baseline serum sTREM2 was higher in anti-MDA5+ DM than controls (median 72.49 ng/mL [IQR 51.14–99.35] vs 31.39 ng/mL [22.10–43.74]; P < 0.0001) and highest in ILD (94.16 ng/mL [IQR 62.71–118.47]), but did not differ between RP-ILD and non-RP-ILD. Serum sTREM2 correlated with disease activity markers and inversely with %FVC and %DLco. At 12 months, sTREM2 decreased in stable/improved patients but increased in aggravated patients, but baseline sTREM2 did not predict aggravation. Conclusion Serum sTREM2 is a candidate, non-invasive monitoring biomarker that reflects ILD severity and changes in parallel with the clinical course in anti-MDA5+ DM.