Legumain Restrains Granuloma Formation by Inhibiting mTORC1/STAT1‐Mediated M1 Macrophage Polarization in Sarcoidosis

ABSTRACT Sarcoidosis is a systemic granulomatous disease that has limited treatment options. Emerging evidence suggests that macrophages are essential for sarcoid granuloma initiation. Legumain (LGMN), a cysteine protease, regulates macrophage polarization in various cancers. However, its involvement in sarcoid granuloma formation remains elusive. Herein, LGMN is upregulated in macrophages within sarcoid‐like granulomas. Genetic deletion of Lgmn exacerbates granulomatous inflammation in a Propionibacterium acnes ( P. acnes )‐induced mouse model, accompanied by increased M1 macrophage polarization. Mechanistically, LGMN binds to integrin αvβ3 on the macrophage surface and restrains M1 polarization by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1)/signal transducer and activator of transcription 1 (STAT1) pathway. Furthermore, intratracheal administration of lipid nanoparticles carrying Lgmn plasmid DNA effectively alleviates granuloma formation induced by P. acnes or trehalose 6,6'‐dimycolate, concomitant with decreased mTORC1/STAT1 activation and M1 polarization. These findings reveal the pivotal role of LGMN in restraining sarcoid granulomatous inflammation through suppression of mTORC1/STAT1‐driven M1 macrophage polarization. Therefore, LGMN supplementation may be a promising therapeutic strategy for sarcoidosis.