IFN-γ induction of GBP1 drives aberrant macrophage activation in human skin granulomas

Granuloma annulare (GA) and cutaneous sarcoidosis (cSAR), non-communicable skin conditions, possess an overlapping immunopathology, in which the aberrant activation of macrophages by IFN-γ constitutes a central driver of disease. Nevertheless, our understanding of the molecular events occurring in pathologically activated GA and cSAR macrophages remains limited. Here, we analyzed published single-cell RNA sequencing data of GA and cSAR and performed in-vitro experiments with primary human cells, allowing us to show that oxidative phosphorylation (OXPHOS) is a dominant metabolic pathway in IFN-γ-activated macrophages. Furthermore, we identify an IFN-γ-induced, OXPHOS-sensitive response network in human GA and cSAR macrophages. Within this network, GBP1 plays a central role in controlling IFN-γ-mediated macrophage activation. Meanwhile, inhibition of OXPHOS and GBP1 both promoted resolution of granulomas and prevented granuloma induction in a human in-vitro granuloma model. Taken together, our study suggests that OXPHOS and GBP1 represent therapeutic strategies for treating cutaneous granulomatous diseases.