Opposing role for myeloid and smooth muscle cell STING in pulmonary hypertension

There is an emerging role for Stimulator of interferon genes (STING) signaling in pulmonary hypertension (PH) development. Related, prior resesarch has demonstrated the relevance of the immune checkpoint protein Programmed death ligand 1 (PD-L1) expression by immunoregulatory myeloid cells in PH. However, there remains a need to elucidate the cell-specific role of STING expression, and the STING/PD-L1 signaling axis in PH, before readily available disease-modifying therapies can be applied to patients with disease. Here, through generation of bone marrow chimeric mice, we show that STING-/- mice receiving wild-type (WT) bone marrow are protected against PH secondary to chronic hypoxia. We further demonstrate a cellular dichotomous role for STING in PH development with STING expression by smooth muscle cells contributing to PH, and its activation on myeloid cells being pivotal in severe disease prevention. Finally, we provide evidence that a STING-PD-L1 axis modulates disease severity, suggesting future potential therapeutic applications. Overall, these data provide concrete evidence of STING involvement in PH in a cell-specific manner, establishing biologic plausibility for cell-targeted STING-related therapies in PH treatment.