Spatial Transcriptomics identifies Prosaposin (PSAP) as a Novel Therapeutic Vulnerability in Pulmonary Sarcoidosis

Sarcoidosis is a chronic inflammatory disorder characterized by the presence of tiny collections of immune cells known as granulomas. An incomplete understanding of etiology and immune-pathologic pathways have limited the development of quality biomarkers and novel targeted therapies. We found a Fsp1-Cre mediated TSC1/2 deletion mice unexpectedly led to development of a disease state, which was identified and characterized by spatial transcriptomics and single-cell RNA sequencing, similar to sarcoidosis. Notably, we identified CCL24 as a novel key chemotactic regulator in this model of sarcoidosis and found decreased CCL24 in the sarcoid group, thus translating our model and hypothesis to the human form of the disease. Intriguingly, we found that CCL24 and azithromycin significantly blocked the progression of granuloma formation in this model. Our findings not only improve an integrated understanding of the progression of sarcoidosis but also provide the basis for developing novel potential clinical interventions in sarcoidosis therapeutics.