Inflammatory cytokines TNF-α and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators

Abstract

Without CFTR-mediated HCO3secretion, airway epithelia of newborns with cystic fibrosis (CF) produce an abnormally acidic airway surface liquid (ASL), and the decreased pH impairs respiratory host defenses. However, within a few months of birth, ASL pH increases to match that in non-CF airways. Although the physiological basis for the increase is unknown, this timecourse matches the development of inflammation in CF airways. To learn whether inflammation alters CF ASL pH, we treated CF epithelia with TNFα and IL-17, two inflammatory cytokines that are elevated in CF airways. TNFα+IL-17 markedly increased ASL pH by upregulating pendrin, an apical Cl -/HCO3exchanger. Moreover, when CF epithelia were exposed to TNFα+IL-17, clinically approved CFTR modulators further alkalinized ASL pH. As predicted by these results, in vivo data revealed a positive correlation between airway inflammation and CFTR modulator-induced improvement in lung function. These findings suggest that inflammation is a key regulator of HCO3secretion in CF airways. Thus, they explain earlier observations that ASL pH increases after birth and indicate that for similar levels of inflammation, the pH of CF ASL is abnormally acidic. These results also suggest that a non-cellautonomous mechanism, airway inflammation, is an important determinant of the response to CFTR modulators.

Impact of Airway Inflammation on the Efficacy of CFTR Modulators

“…Recently, Rehman et al reported that inflammation enhances the response to CFTR modulators in vitro and in vivo [60]. The in vitro studies employed TNFα and IL-17 as inflammatory stimuli [60], and their findings are in agreement with our previous in vitro studies demonstrating that the CF airway inflammatory milieu enhances the efficacy of CFTR modulators [32,58].…”

“…As discussed above, although VX-770 destabilizes rescued F508del [59,63], inflammation can overcome the detrimental effects of chronic exposure to ivacaftor [32]. Hence, we speculate that through a mechanism involving inflammationdependent CFTR stabilization, the efficacy of chronic VX-770 treatment is improved in CF patients, resulting in increases in forced expiratory volume in 1 s (FEV 1 ), as observed by Rehman et al [60].…”

“…Importantly, Rehman et al observed a positive correlation between airway inflammation and lung function improvement in CF patients treated with VX-770 [60]. As the majority of the G551D and R117H patients in the study by Rehman et al had F508del in one allele [60], we speculate that maturation of F508del may have been increased by inflammation, contributing, at least in part, to the observed clinical improvement. This is supported by the observation that inflammation enhances the ER folding capacity [19,26,27,61], which may facilitate rescue of misfolded CFTR [32].…”

“…The in vitro findings indicating that CF airway epithelial inflammation enhances the efficacy of CFTR modulators, together with the initially predicted [32] and the recently found positive correlation between airway inflammation and enhanced CFTR modulatorimproved lung function in CF patients [60], have implications for the clinic. For instance, no study has addressed whether anti-inflammatory medications (e.g., azithromycin) interfere with the efficacy of CFTR modulators.…”

“…Recently, Rehman et al reported that inflammation enhances the response to CFTR modulators in vitro and in vivo [60]. The in vitro studies employed TNFα and IL-17 as inflammatory stimuli [60], and their findings are in agreement with our previous in vitro studies demonstrating that the CF airway inflammatory milieu enhances the efficacy of CFTR modulators [32,58]. As the stability of band C was not evaluated and band B was not detected in the study by Rehman et al [60], the mechanism for the enhanced F508del CFTR rescue by TNFα and IL-17 remains unclear.…”