Cell dichotomous role of STING in pulmonary hypertension

Rationale Patients with constitutive activation of DNA sensing pathway through stimulator of interferon genes (STING), such as those with STING-Associated Vasculopathy with onset in Infancy (SAVI), frequently have complications related to pulmonary hypertension (PH). However, the role of STING-signaling in adult PH patients is heretofore undescribed. Objective To investigate the role of STING in PH development. Methods and Results PH was induced in global STING deficient or cell-specific STING deficient mice using either bleomycin or chronic hypoxia exposure. PH development was evaluated with right ventricular systolic pressure, Fulton index, histological and flow cytometric measurements. STING expression in patient lungs were examined using both immunohistochemistry and flow cytometry. Herein, we describe how STING overactivation in a SAVI mouse model results in a baseline elevation in pulmonary pressures, while global STING deficiency protects mice from PH development. Furthermore, STING-associated PH appears to be independent of type I Interferon (IFN) signaling. We further demonstrate a cellular dichotomous role of 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 demonstrate a STING-PD-L1 axis as necessary for disease progression, suggesting future potential therapeutic applications. Conclusions Overall, these data provide concrete evidence of STING involvement in PH, establishing biologic plausibility for STING-related therapies in PH treatment. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * aSMA : Alpha smooth muscle actin CTV : Cell trace violet eSTING : VeCad-Cre+/-STINGfl/fl (endothelial specific deletion of STING) IHC : Immunohistochemical ILD : Interstitial lung disease IPF : Idiopathic pulmonary fibrosis IRF3 : Interferon regulatory factor 3 MDSC : Myeloid derived suppressor cell Mo-MDSC : Monocytic myeloid-derived suppressor cell mSTING : LysM- Cre+/-STINGfl/fl (myeloid specific deletion of STING) MTC : Masson trichrome PAEC : Pulmonary arterial endothelial cell PD-L1 : Programmed death ligand-1 PH : Pulmonary hypertension PMN-MDSC : Polymorphonuclear myeloid-derived suppressor cell PVSMC : Pulmonary vascular smooth muscle cell RVSP : Right ventricular systolic pressure SAVI : STING-associated Vasculopathy onset in Infancy SMC : Smooth muscle cell smSTING : SMA-Cre+/-STINGfl/fl (smooth muscle specific deletion of STING) STING : Stimulator of Interferon Genes STING-/- : Global STING deficiency VEGF : Vascular endothelial growth factor WT : Wild type [1]: pending:yes