PT  - JOURNAL ARTICLE
AU  - Pham, Ann T.
AU  - Oliveira, Aline C.
AU  - Fu, Chunhua
AU  - Alves, Matthew D.
AU  - Dupee, Zadia
AU  - Mukhsinova, Laylo
AU  - Ebrahimi, Elnaz
AU  - Patel, Harsh
AU  - Patel, Reeha
AU  - Nguyen, Amy
AU  - Jin, Lei
AU  - Bryant, Andrew J.
TI  - Cell dichotomous role of STING in pulmonary hypertension
AID  - 10.1101/2022.11.29.518422
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.11.29.518422
4099  - http://biorxiv.org/content/early/2022/11/29/2022.11.29.518422.short
4100  - http://biorxiv.org/content/early/2022/11/29/2022.11.29.518422.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.aSMAAlpha smooth muscle actinCTVCell trace violeteSTINGVeCad-Cre+/-STINGfl/fl (endothelial specific deletion of STING)IHCImmunohistochemicalILDInterstitial lung diseaseIPFIdiopathic pulmonary fibrosisIRF3Interferon regulatory factor 3MDSCMyeloid derived suppressor cellMo-MDSCMonocytic myeloid-derived suppressor cellmSTINGLysM- Cre+/-STINGfl/fl (myeloid specific deletion of STING)MTCMasson trichromePAECPulmonary arterial endothelial cellPD-L1Programmed death ligand-1PHPulmonary hypertensionPMN-MDSCPolymorphonuclear myeloid-derived suppressor cellPVSMCPulmonary vascular smooth muscle cellRVSPRight ventricular systolic pressureSAVISTING-associated Vasculopathy onset in InfancySMCSmooth muscle cellsmSTINGSMA-Cre+/-STINGfl/fl (smooth muscle specific deletion of STING)STINGStimulator of Interferon GenesSTING-/-Global STING deficiencyVEGFVascular endothelial growth factorWTWild type