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Epithelial responses to CFTR modulators are improved by inflammatory cytokines and impaired by anti-inflammatory drugs
Journal article   Open access   Peer reviewed

Epithelial responses to CFTR modulators are improved by inflammatory cytokines and impaired by anti-inflammatory drugs

Tayyab Rehman, Alejandro A Pezzulo, Andrew L Thurman, Rachel L Zemans and Michael J Welsh
JCI insight, Vol.9(14), e181836
07/22/2024
DOI: 10.1172/jci.insight.181836
PMCID: PMC11383177
PMID: 38888974
url
https://doi.org/10.1172/jci.insight.181836View
Published (Version of record) Open Access

Abstract

Cystic fibrosis (CF) is a genetic disorder that disrupts CF transmembrane conductance regulator (CFTR) anion channels and impairs airway host defenses. Airway inflammation is ubiquitous in CF and suppressing it has generally been considered to improve outcomes. However, the role of inflammation in people taking CFTR modulators, small-molecule drugs that restore CFTR function, is not well-understood. We previously showed that inflammation enhances the efficacy of CFTR modulators. To further elucidate this relationship, we treated human ∆F508-CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 enhanced CFTR modulator-evoked anion secretion through mechanisms that raise intracellular Cl- (Na+/K+/2Cl- co-transport) and HCO3- (carbonic anhydrases and Na+/HCO3- co-transport). This enhancement required p38 MAPK signaling. Importantly, CFTR modulators did not affect CF airway surface liquid viscosity under control conditions, but prevented the rise in viscosity in epithelia treated with TNFα+IL-17. Lastly, anti-inflammatory drugs limited CFTR modulator responses in TNFα+IL-17-treated epithelia. These results provide critical insights into mechanisms by which inflammation increases responses to CFTR modulators. They also suggest an equipoise between potential benefits versus limitations of suppressing inflammation in people taking modulators, call into question current treatment approaches, and highlight a need for additional studies.Cystic fibrosis (CF) is a genetic disorder that disrupts CF transmembrane conductance regulator (CFTR) anion channels and impairs airway host defenses. Airway inflammation is ubiquitous in CF and suppressing it has generally been considered to improve outcomes. However, the role of inflammation in people taking CFTR modulators, small-molecule drugs that restore CFTR function, is not well-understood. We previously showed that inflammation enhances the efficacy of CFTR modulators. To further elucidate this relationship, we treated human ∆F508-CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 enhanced CFTR modulator-evoked anion secretion through mechanisms that raise intracellular Cl- (Na+/K+/2Cl- co-transport) and HCO3- (carbonic anhydrases and Na+/HCO3- co-transport). This enhancement required p38 MAPK signaling. Importantly, CFTR modulators did not affect CF airway surface liquid viscosity under control conditions, but prevented the rise in viscosity in epithelia treated with TNFα+IL-17. Lastly, anti-inflammatory drugs limited CFTR modulator responses in TNFα+IL-17-treated epithelia. These results provide critical insights into mechanisms by which inflammation increases responses to CFTR modulators. They also suggest an equipoise between potential benefits versus limitations of suppressing inflammation in people taking modulators, call into question current treatment approaches, and highlight a need for additional studies.

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