βc receptor antagonism mitigates sarcoidosis granuloma formation by targeting inflammatory signals and aberrant lipid metabolism

Hao Wang¹Damon J Tumes²Simon Keam³Jia Wen Lim²Quynh Anh Nguyen¹Ross Vlahos¹Jonathan Mcqualter¹Adam Quek³Carly Whyte²Harshita Pant²Tim R Hercus²Nicholas J Wilson³Paul N Reynolds⁴Catherine M Owczarek³Angel F Lopez²Steven Bozinovski¹Kwok Ho Yip^2*

• ¹RMIT University School of Health and Biomedical Sciences, Bundoora, Australia
• ²Centre for Cancer Biology (CCB), Adelaide, Australia
• ³CSL Limited, Parkville, Australia
• ⁴Royal Adelaide Hospital, Adelaide, Australia

Introduction: Sarcoidosis is a multisystem chronic inflammatory disorder of unknown etiology that primarily affects the lungs and currently has no cure. Macrophages are central to granuloma formation, and βc cytokines tightly regulate their activation and function. This study investigates the role of the βc receptor in granuloma development and evaluates βc antagonism as a potential therapeutic strategy for sarcoidosis. Methods: We utilized an in vitro model of human granuloma formation using sarcoidosis patient human peripheral blood mononuclear cells (PBMCs) and an in vivo vimentin-induced pulmonary sarcoidosis model in unique humanized βc transgenic (hβcTg) mice to assess the efficacy of βc antagonism in reducing granuloma formation and evaluate the underlying mechanism of action. Results: Anti-βc receptor antibody, CSL311, significantly reduced the formation of human granulomas from PBMCs exposed to purified protein derivative and decreased the pro-inflammatory cytokine production by the granulomas. Mechanistically, CSL311 inhibited hyperactivation of mTOR signaling and reduced lipid droplet formation in granuloma macrophages. In hβcTg mice challenged with vimentin, CSL311 effectively reduced both granuloma size and immune cell infiltration in the lung. RNA sequencing analysis of lung tissue further showed that CSL311 treatment suppressed the activation of vimentin-induced inflammatory, fibrotic, and lipid metabolic pathways. Conclusion: We identified that βc cytokines are critical regulators in driving inflammatory and metabolic processes that lead to granuloma formation in sarcoidosis. Precisely targeting the βc receptor effectively disrupts these pathogenic networks and offers a promising new strategy for mitigating sarcoidosis immunopathology.