Journal Article

An immunometabolic pathomechanism for chronic obstructive pulmonary disease

Bocchino, Marialuisa, Galgani, Mario, Santopaolo, Marianna, Mottola, Maria, Porcellini, Antonio, Micillo, Teresa, De Rosa, Veronica, Matarese, Giuseppe, Zuchegna, Candida, De Simone, Salvatore, Perna, Francesco, D’Amato, Maria, Garziano, Federica, Romano, Antonella, Stanziola, Anna Agnese, Bruzzaniti, Sara, Barra, Enrica, Zuccarelli, Bruno, Esposito, Antonella, Calì, Gaetano

2019

Overview

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with abnormal immune responses, leading to airflow obstruction. Lungs of COPD subjects show accumulation of proinflammatory T helper (Th) 1 and Th17 cells resembling that of autoreactive immune responses. As regulatory T (Treg) cells play a central role in the control of autoimmune responses and their generation and function are controlled by the adipocytokine leptin, we herein investigated the association among systemic leptin overproduction, reduced engagement of glycolysis in T cells, and reduced peripheral frequency of Treg cells in different COPD stages. These phenomena were also associated with an impaired capacity to generate inducible Treg (iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited the expression of forkhead-boxP3 (FoxP3) and its splicing variants containing the exon 2 (FoxP3-E2) that correlated inversely with inflammation and weakened lung function during COPD progression. Our data reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a decline in the expression of FoxP3 splicing forms, and an impairment in Treg cell generation and function. These results have potential implications for better understanding the autoimmune-like nature of COPD and the pathogenic events leading to lung damage.

• Publisher: National Academy of Sciences
• Subject: Air flow / Alternative Splicing - immunology / Biological Sciences / Chronic obstructive pulmonary disease / Female / Forkhead protein / Forkhead Transcription Factors - biosynthesis / Forkhead Transcription Factors - immunology / Foxp3 protein / Glycolysis / Helper cells / Humans / Leptin / Leptin - biosynthesis / Leptin - immunology / Lung diseases / Lungs / Lymphocytes / Lymphocytes T / Male / Medical Sciences / Middle Aged / Obstructive lung disease / PNAS Plus / Pulmonary Disease, Chronic Obstructive - immunology / Pulmonary Disease, Chronic Obstructive - metabolism / Pulmonary Disease, Chronic Obstructive - pathology / Respiratory function / Splicing / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / T-Lymphocytes, Regulatory - pathology / Th1 Cells - immunology / Th1 Cells - metabolism / Th1 Cells - pathology / Th17 Cells - immunology / Th17 Cells - metabolism / Th17 Cells - pathology