The Increased Secretion of Lactate Observed in Obesity and Aging Leads to the Generation of Pathogenic B Cells

ABSTRACT Lactate is a metabolite with immunoregulatory functions. We evaluated lactate secretion and its effects on B cells from individuals with different body composition: Y LEAN , Y OBESE , and E LEAN individuals. Results show higher serum metabolic profiles in Y OBESE and E LEAN versus Y LEAN individuals, evaluated by levels of lactate dehydrogenase, the enzyme that converts pyruvate into lactate, which is associated with increased secretion of lactate in blood‐derived B cells. Double negative (DN) B cells, which expand in the blood of Y OBESE and E LEAN individuals, are the major contributors to this metabolic profile. When lactate was added in vitro to B cells from Y LEAN , Y OBESE , and E LEAN individuals, we found increased secretion of pathogenic autoimmune antibodies in B cells from Y LEAN , compared to those from Y OBESE and E LEAN individuals, likely because B cells from Y OBESE or E LEAN individuals have already been exposed to, and chronically stimulated by lactate in vivo, becoming refractory to further stimulation. Mechanistically, the effects of lactate are mediated by phosphorylated signal transducer and activator of Transcription 3 (p‐STAT3). These effects are inhibited in the presence of a neutralizing antibody that blocks the lactate transporter SLC5A12, responsible for lactate uptake and activation of inflammatory and pathogenic responses, and p‐STAT3.