Dietary methionine mitigates immune-mediated damage by enhancing renal clearance of cytokines

Abstract

The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using Yersinia pseudotuberculosis infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite S-adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death.