Reactive species as regulators of immune cell metabolism, tolerance, and autoimmunity.

Abstract

Reactive oxygen and nitrogen species (ROS and RNS) connect metabolism to immunity through dynamic spatially restricted chemical events. They regulate receptor signaling cascades, set kinase-phosphatase thresholds, and coordinate mitochondrial activity. Antioxidant systems keep this "signaling window" open by recycling oxidized targets using NADPH supplied by the pentose phosphate pathway, auxiliary enzymes, and 1-carbon metabolism. When generation and removal fall out of balance, hydroxyl radical and peroxynitrite accumulation causes oxidative stress and inflammatory signaling. The oxidized macromolecules perturb innate sensors and exacerbate inflammation, driving autoimmune diseases. Here, we review how reactive species shape immunometabolic regulation and autoimmunity. We first explain the chemical and metabolic foundations of reactive species generation in innate and adaptive immune responses. We then describe how redox imbalance breaks tolerance in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Finally, we outline targeted strategies that alleviate redox imbalance in autoimmune pathologies.