β-oxidation-mediated differentiation of effector CD4+ T cells in the lung enhances neuroinflammation.

Although the lung-brain axis has emerged as a potential regulator of central nervous system (CNS) autoimmunity, the cellular and molecular mechanisms by which the lung microenvironment influences pathogenesis of multiple sclerosis (MS) remain unclear. Here, using experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we found a marked expansion of effector CD4⁺ T cells in the lungs of EAE mice. The EAE lung microenvironment promoted metabolic reprogramming in CD4⁺ T cells, characterized by enhanced fatty acid uptake and upregulation of carnitine transporters. Metabolomic profiling further demonstrated enrichment of carnitine-related metabolites in the EAE lungs, with a strong correlation between metabolic profiles in the lungs and brains, suggesting coordinated metabolic remodeling along the lung-brain axis. Mechanistically, the EAE lung microenvironment significantly enhanced effector CD4⁺ T cell differentiation in vitro through a β-oxidation-dependent pathway. Importantly, pharmacological inhibition of β-oxidation in the lungs significantly attenuated EAE severity, reduced CD4⁺ T cell infiltration into the CNS, and impaired effector CD4⁺ T cell differentiation in the lungs. Collectively, these findings demonstrate that β-oxidation-mediated differentiation of effector CD4⁺ T cells in the lung exacerbates neuroinflammation, highlighting the lung-brain axis as a potential therapeutic target for MS.