Fructose specifically exacerbates pathogenic-Th17 cell differentiation and autoimmune diseases through ROS-EGFR signal

Th17 cells are quite heterogeneous, with pathogenic roles in autoimmunity and non-pathogenic roles in maintaining tissue homeostasis. Although efforts have been made to study genetic and cellular factors in regulating Th17 cell differentiation, little is known about the role of environmental factors and their underlying mechanisms. Here, we revealed that high-fructose intake selectively enhanced the differentiation and function of IL1b+IL-6+IL-23-induced pathogenic Th17 cells (pTh17), without affecting TGFb1+IL-6-induced non-pTh17 cells, and exacerbated autoimmune diseases models. Notably, fructose enhanced both aerobic glycolysis and OXPHOS activity in pTh17 cells, leading to increased ROS production and subsequently promoting their differentiation. N-acetyl cysteine (NAC), a ROS scavenger, specifically impaired pTh17 cell immunity and mitigated autoimmune disease under high-fructose consumption. Mechanistically, ROS accumulation resulted in higher EGFR expression and activation, which subsequently translocated in nucleus to bind with STAT3, enhancing its transcriptional activity of CNS6 and CNS9 regions of Rorc. Taking together, we illustrated a previously unrecognized mechanism underlying the adverse effects of high-fructose intake in pTh17 cell-related pathologies and diseases.