IRG1/Itaconate Axis as an Immunometabolic Regulator of Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by pulmonary vascular remodeling and right ventricular hypertrophy, with immune cell–mediated mechanisms playing a central role. Immune-Responsive Gene 1 (IRG1), which encodes the enzyme responsible for itaconate production in macrophages, has established functions in inflammatory metabolism; however, its role in cardiopulmonary homeostasis and PH remains unclear. In this study, we identify the IRG1/itaconate axis as a regulator of inter-organ communication between the bone marrow (BM), heart, and lung. Using IRG1-deficient (Irg1⁻/⁻) mice, we demonstrate that loss of Irg1 leads to cardiopulmonary alterations driven by immune and metabolic dysregulation. Cardiac phenotyping of Irg1⁻/⁻ mice revealed significant right and left ventricular hypertrophy and dysfunction, accompanied by increased macrophage and dendritic cell infiltration. Transcriptomic analysis showed activation of inflammatory pathways, including TNF-α/NF-κB signaling, hypoxia-associated responses, and upregulation of endothelin-related genes. Epigenetic alterations were also observed, with increased expression of the histone demethylase Jmjd3 and reduced H3K27me3 levels, suggesting a mechanism linking IRG1 deficiency to sustained inflammation and cardiac remodeling. In the lung, Irg1 deficiency predisposed to pulmonary vascular remodeling and heightened susceptibility to hypoxia-induced PH, associated with an expanded myeloid compartment and enhanced inflammatory signaling. These findings are consistent with observations in PAH patients, who exhibit increased myeloid cell populations compared to non-PH controls. Adoptive transfer of BM from Irg1⁻/⁻ mice into irradiated WT mice induced cardiac hypertrophy, highlighting the strong contribution of BM to cardiac dysfunction under Irg1 deficiency. Additionally, IRG1-deficient macrophages induced hypertrophic and fibrotic responses in cardiac fibroblasts via paracrine signaling. IRG1 deficiency disrupted hematopoietic stem progenitor cell (HSPC) function and differentiation. This was associated with impaired purine metabolism, increased ATP levels, and activation of the NLRP3 inflammasome, leading to enhanced inflammatory signaling and immune cell mobilization into peripheral organs, particularly the heart and lung. Collectively, these findings indicate that IRG1/itaconate axis deficiency drives the cardiopulmonary phenotype by dysregulating HSPC differentiation and mobilization through immunometabolic alterations, ultimately leading to pulmonary vascular remodeling and cardiac hypertrophy, highlighting its potential as a therapeutic target for PH and related cardiopulmonary complications.