Epithelial responses to CFTR modulators are improved by inflammatory cytokines and impaired by antiinflammatory drugs
Tayyab Rehman, Alejandro A. Pezzulo, Andrew L. Thurman, Rachel L. Zemans, Michael J. Welsh
Tayyab Rehman, Alejandro A. Pezzulo, Andrew L. Thurman, Rachel L. Zemans, Michael J. Welsh
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Research Article Pulmonology

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

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 ΔF508-CF epithelia with TNF-α and IL-17, two inflammatory cytokines that are elevated in CF airways. TNF-α+IL-17 enhanced CFTR modulator–evoked anion secretion through mechanisms that raise intracellular Cl– (Na+/K+/2Cl– cotransport) and HCO3– (carbonic anhydrases and Na+/HCO3– cotransport). 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 TNF-α+IL-17. Finally, antiinflammatory drugs limited CFTR modulator responses in TNF-α+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 and limitations of suppressing inflammation in people taking modulators, call into question current treatment approaches, and highlight a need for additional studies.

Authors

Tayyab Rehman, Alejandro A. Pezzulo, Andrew L. Thurman, Rachel L. Zemans, Michael J. Welsh

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Figure 7

TNF-α+IL-17 treatment sensitizes CF epithelia to the beneficial effects of CFTR modulators.

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TNF-α+IL-17 treatment sensitizes CF epithelia to the beneficial effects ...
(A) Model showing CF airway epithelium under control conditions. In this model, basolateral NKCC1 imports Cl–, NBC imports HCO3–, and CA generates HCO3– within the cytosol. However, in the absence of apical CFTR channels, there is diminished anion secretion, which renders ASL viscous and thus impairs host defense. (B) CFTR modulators restore some apical CFTR activity but fail to lower ASL viscosity. (C) TNF-α+IL-17 treatment increases NKCC1, NBC, and CA expression. They also increase expression of secreted, gel-forming mucins MUC5AC and MUC5B (not shown). TNF-α+IL-17 may induce some non-CFTR HCO3– secretion, perhaps via pendrin, as previously reported (17). However, by itself, this does not prevent an increase in ASL viscosity. (D) Remarkably, TNF-α+IL-17 treatment increases modulator-induced apical CFTR expression and activity and, in concert with increased NKCC1, NBC, and CA, lowers ASL viscosity. CFTR, cystic fibrosis transmembrane conductance regulator; NKCC1, Na+/K+/2Cl– cotransporter 1; NBC, Na+/HCO3– cotransporters; CA, carbonic anhydrase; ASL, airway surface liquid.