Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) is a syndrome characterized by a mean pulmonary artery pressure >20 mmHg and elevated pulmonary vascular resistance >2 Wood Units in the absence of left heart disease, chronic lung disease or hypoxia, and chronic thromboembolic disease. PAH is an obliterative pulmonary arteriopathy that leads to morbidity and mortality, often due to right ventricular failure (RVF). Emerging evidence from preclinical research, using chemical inhibition or genetic depletion of inflammatory mediators, reveals a role for inflammation in the adverse pulmonary vascular remodelling in PAH. More recently, studies have also identified inflammation of the right ventricle (RV) as a potential contributor to RV decompensation and failure. While inflammation contributes to the pathogenesis of PAH, no approved PH-targeted therapies specifically target inflammation. Macrophages are myeloid cells that play a critical role in inflammation and PAH. Their cellular plasticity enables the acquisition of tissue-specific phenotypes and functions that may promote either resolution or exacerbation of inflammatory signalling. Macrophage plasticity in PAH is poorly understood. We examine how alterations in glucose metabolism, particularly the uncoupling of glycolysis from glucose oxidation-a notable feature of PAH observed in various cell populations-impact macrophage polarization and the inflammatory phenotype associated with PAH. The study of immune cell metabolism, known as immunometabolism, is an emerging field that has yet to be explored in PAH. Improving understanding of the inflammatory mechanisms in PAH, particularly novel pathways related to macrophage immunometabolism, may identify new targets for anti-inflammatory therapies for PAH.