Macrophage immunometabolic programming in pulmonary arterial hypertension: prioritizing TET2 and METTL3/m⁶A
Year: 2026
Type: article
Abstract: Pulmonary arterial hypertension (PAH) is sustained by pulmonary vascular remodeling and right ventricular (RV) maladaptation that often remain incompletely reversible despite contemporary pathway-directed therapy. A central mechanistic question is how macrophage states that promote remodeling are maintained. This focused narrative review examines three potentially coexisting explanations: continued conditioning by the pathological niche, selective recruitment of monocyte subsets with pre-existing inflammatory signatures, and cell-intrinsic regulatory states that persist after stimulus withdrawal. Single-cell and spatial studies identify lesion-, subset- and stage-dependent macrophage states, but cannot alone distinguish these explanations. Metabolic regulation of chromatin and RNA provides candidate links between local cues and sustained function. We compare TET2-dependent DNA regulation and METTL3/m6A-dependent RNA fate as complementary routes through which metabolic cues may influence inflammatory restraint and effector output. Human associations and hematopoietic or myeloid perturbation studies support their investigation, but do not establish durable programming in human lesional macrophages. We therefore distinguish ongoing activation from persistent programming and trained immunity, evaluate pulmonary and RV evidence separately, and define the validation requirements for testing whether disruption of macrophage-state maintenance can reverse established disease.
Source: Frontiers in Immunology
Authors: Hui Meng, Juan Liao, Li Peng, Yan Deng
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225424001