mTORC1-Dependent Regulation of the CCL24-CCR3 Axis Controls Granuloma Formation and Maintenance in Sarcoidosis

Abstract

Sarcoidosis is a chronic granulomatous disease marked by persistent inflammation and immune cell aggregation, yet its molecular underpinnings remain incompletely understood, hindering the development of effective targeted therapies. Here, we report that deletion of TSC1 or TSC2 in mice using a Fsp1-Cre leads to spontaneous formation of sarcoid-like granulomas, driven by hyperactivation of the mTORC1 pathway in fibroblasts and interstitial macrophages. Through inflammatory cytokine/chemokine array, we identified CCL24, a chemokine ligand for CCR3, as a key immunoregulatory molecule downregulated in both our murine model and sarcoid cohort plasma. Mechanistically, mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages, uncovering a novel regulatory axis in granuloma formation and maintenance. Pharmacological inhibition using rapamycin and azithromycin markedly attenuated granuloma burden and normalized CCL24-CCR3 signaling, underscoring the therapeutic relevance of this axis. Together, our study establishes a mechanistic link between mTORC1 activation, CCL24-CCR3 dysregulation, and granuloma persistence, offering not only a new insight into molecular mechanisms in sarcoidosis but also identifying promising targets for clinical intervention.