Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis

Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1β secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain–containing protein 3) inflammasome. The study aimed to explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis monocytes and on circulating proinflammatory markers. Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1β secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. P2X7R expression is regulated by intracellular Cl− levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R–induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.