Journal Article Epublish
PubMed: 40402605 DOI: 10.1172/jci.insight.184792
Opposing roles for myeloid and smooth muscle cell STING in pulmonary hypertension.
JCI Insight 10(13)
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
Affiliations
- Department of Medicine.
- Department of Pharmacology and Therapeutics, and.
- Department of Biostatistics, College of Medicine, University of Florida, Gainesville, Florida, USA.
- Department of Biochemistry and Molecular Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
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.
MeSH
Cells, Hypertension, Muscle Cells, Hypertension, Pulmonary, Bone Marrow, Muscles, Muscle, Smooth, Biomedical Research, Myeloid Cells, Therapeutics, Myocytes, Smooth Muscle