cells Article Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells Onofrio Laselva , Caterina Allegretta, Sante Di Gioia , Carlo Avolio and Massimo Conese *   Citation: Laselva, O.; Allegretta, C.; Di Gioia, S.; Avolio, C.; Conese, M. Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells. Cells 2021, 10, 2132. https://doi.org/ 10.3390/cells10082132 Academic Editors: Teresinha Leal, Tristan Montier, Martial Delion, Angélique Mottais and Gergely L. Lukacs Received: 22 June 2021 Accepted: 16 August 2021 Published: 19 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; onofrio.laselva@unifg.it (O.L.); caterina.allegretta@unifg.it (C.A.); sante.digioia@unifg.it (S.D.G.); carlo.avolio@unifg.it (C.A.) * Correspondence: massimo.conese@unifg.it Abstract: Cystic Fibrosis (CF) is caused by mutations on the CF transmembrane conductance regula- tor (CFTR) gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early ox- idative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stim- ulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/H 2 O 2 and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Fi- nally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy. Keywords: dimethyl fumarate; cystic fibrosis; airway epithelial cells; cytokine; oxidative stress 1. Introduction Cystic fibrosis (CF) is the most common fatal autosomal recessive disorder among Caucasians, estimated to affect more than 70,000 people in the world. Over 2000 sequence variations have been discovered in the CF Transmembrane Conductance Regulator (CFTR) gene, ~300 of which are pathogenic [1], causing either lack or dysfunction of the mutated protein. The most common mutation is F508del, which accounts for approximately two thirds of all CFTR alleles in patients with CF. Lung disease represents the chief cause of morbidity and mortality of these patients, ultimately leading to chronic respiratory failure and lung transplantation. Its pathophysiology is characterized by severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruc- tion and bronchiectasis. CF airways lack proper hydration of the mucus overlaying thexd epithelium, with consequent loss of the mucociliary clearance and opportunistic bacterial infections. Upon colonization by pathogens, the innate immunity of CF lungs prompts the secretion of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and chemokines (IL-8) by airway epithelial cells, macrophages and dendritic cells. These determine, at first, the attraction and activation of neutrophils, which, upon phagocytosis, kills pathogens [2]. However, for reasons still to be unveiled, this inflammatory response is not suited to combating and eradicating infections from the airways. Moreover, the acquired immunity is operated by T cell-mediated responses and, in particular, mediated by Th17 cells. CF lung secretions are enriched in IL-17A and IL-17F cytokines [3] which determine further activation of airway epithelial cells and stimulate lung fibroblast to secrete granulocyte Cells 2021, 10, 2132. https://doi.org/10.3390/cells10082132 https://www.mdpi.com/journal/cells