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Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15625-15634. doi: 10.1073/pnas.1906303116. Epub 2019 Jul 15.

An immunometabolic pathomechanism for chronic obstructive pulmonary disease.

Author information

1
Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, 80131 Naples, Italy.
2
Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy.
3
Unità di Anatomia Patologica, Azienda Ospedaliera Specialistica dei Colli Monaldi-Cotugno-C.T.O., 80131 Naples, Italy.
4
Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università degli Studi di Napoli "Federico II," 80126 Naples, Italy.
5
Unità Operativa Complessa di Medicina Trasfusionale, Azienda Ospedaliera Specialistica dei Colli Monaldi-Cotugno-C.T.O., 80131 Naples, Italy.
6
Unità di Neuroimmunologia, Istituto di Ricovero e Cura a Carattere Scientifico-Fondazione Santa Lucia, 00143 Rome, Italy.
7
Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; giuseppe.matarese@unina.it mario.galgani@unina.it.
8
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy.

Abstract

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.

KEYWORDS:

COPD; immunometabolism; leptin; regulatory T cells

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