An immunometabolic pathomechanism for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an inflammatorycondition associated with abnormal immune responses, leading toairflow obstruction. Lungs of COPD subjects show accumulation ofproinflammatory T helper (Th) 1 and Th17 cells resembling that ofautoreactive immune responses. As regulatory T (Treg) cells play acentral role in the control of autoimmune responses and theirgeneration and function are controlled by the adipocytokine lep-tin, we herein investigated the association among systemic leptinoverproduction, reduced engagement of glycolysis in T cells, andreduced peripheral frequency of Tregcells in different COPD stages.These phenomena were also associated with an impaired capacityto generate inducible Treg(iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited theexpression of forkhead-boxP3 (FoxP3) and its splicing variants con-taining the exon 2 (FoxP3-E2) that correlated inversely with inflam-mation and weakened lung function during COPD progression. Ourdata reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a de-cline in the expression of FoxP3 splicing forms, and an impairmentin Tregcell generation and function. These results have potentialimplications for better understanding the autoimmune-like natureof COPD and the pathogenic events leading to lung damage.