# Opposing roles for myeloid and smooth muscle cell STING in pulmonary hypertension

## TL;DR

The study shows that STING signaling has different roles in different cell types in pulmonary hypertension, suggesting potential for targeted therapies.

## Contribution

The study reveals a cell-specific role of STING and the STING/PD-L1 axis in pulmonary hypertension development.

## Key findings

- STING expression in smooth muscle cells contributes to pulmonary hypertension.
- STING activation in myeloid cells helps prevent severe disease.
- A STING/PD-L1 signaling axis modulates disease severity.

## 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.

The manuscript investigated the cell-specific role of STING in pulmonary hypertension development, as well as the STING/PD-L1 signaling axis in disease progression.