Opposing Roles for Myeloid and Smooth Muscle Cell STING in Pulmonary Hypertension

Authors

Ann T Pham
Shiza Virk
Aline C Oliveira
Matthew D Alves
Chunhua Fu
Yutao Zhang
Jimena Alvarez-Castanon
Brian B Lee
Keira L Lee
Radwan Mashina
Katherine E Ray
Patrick Donabedian
Elnaz Ebrahimi
Harsh Patel
Reeha Patel
Duncan Lewis
Zhiguang Huo
Harry Karmouty-Quintana
Li Chen
Lei Jin
Andrew J Bryant

Language

English

Publication Date

7-8-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.184792

PMID

40402605

PMCID

PMC12288902

PubMedCentral® Posted Date

5-22-2025

PubMedCentral® Full Text Version

Post-print

Abstract

There is an emerging role for stimulator of interferon genes (STING) signaling in pulmonary hypertension (PH) development. Related to this, prior research has demonstrated the relevance of 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 for patients with the disease. Here, through generation of bone marrow chimeric mice, we show that STING-/- mice receiving WT bone marrow were 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 the potential for future therapeutic applications. Overall, these data provide evidence of STING's involvement in PH in a cell-specific manner, establishing the biologic plausibility of developing cell-targeted STING-related therapies for PH.

Keywords

Animals, Hypertension, Pulmonary, Membrane Proteins, Mice, Myeloid Cells, Myocytes, Smooth Muscle, B7-H1 Antigen, Signal Transduction, Mice, Knockout, Disease Models, Animal, Hypoxia, Male, Humans, Mice, Inbred C57BL, STING Protein, Pulmonology, Vascular biology, Cardiovascular disease

Published Open-Access

yes

Recommended Citation

Pham, Ann T; Virk, Shiza; Oliveira, Aline C; et al., "Opposing Roles for Myeloid and Smooth Muscle Cell STING in Pulmonary Hypertension" (2025). Faculty, Staff and Student Publications. 5956.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5956