Agmatine ameliorates poly(I:C)-induced lung injury through IL-10/STAT3-dependent reprogramming of macrophage inflammatory responses.

The emerging field of immunometabolism posits that endogenous metabolites are pivotal regulators of immune responses, yet their therapeutic exploitation remains nascent. Investigating this paradigm in lung injury, we observed that agmatine, a decarboxylation product of L-arginine, was significantly depleted in poly(I:C)-induced murine lung injury and in a clinical cohort characterized by virus-associated pulmonary involvement, suggesting a potential association with lung pathology. In mice, exogenous agmatine supplementation ameliorated lung pathology and weight loss, effects that were contingent upon reprogramming of macrophage inflammatory responses. Mechanistically, agmatine exerts its anti-inflammatory effects through macrophage-specific mechanisms: it selectively inhibits macrophage-derived TNF-α and CXCL10 without affecting the NF-κB signaling pathway. Transcriptomic analysis of murine macrophages revealed that agmatine significantly upregulates IL-10 expression, and its protective effects were reversed using either IL-10R neutralizing antibody or macrophages from IL-10-deficient mice. In murine macrophages, further investigation confirmed that agmatine promotes STAT3 phosphorylation and nuclear translocation, while STAT3 knockdown partially abrogated its anti-inflammatory efficacy. Our findings position agmatine within the expanding realm of immunometabolic therapy, highlighting its potential as a therapeutic strategy for lung injury by harnessing an endogenous anti-inflammatory circuit.