Trikafta rescues CFTR and lowers monocyte P2X7R-induced inflammasome activation in cystic fibrosis
C Gabillard-Lefort, M Casey, AMA Glasgow… - American journal of …, 2022 - atsjournals.org
C Gabillard-Lefort, M Casey, AMA Glasgow, F Boland, O Kerr, E Marron, AM Lyons…
American journal of respiratory and critical care medicine, 2022•atsjournals.orgRationale: 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. Objectives: To explore the effect of the
CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the
ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers …
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. Objectives: To explore the effect of the
CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the
ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers …
Rationale: 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.
Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers.
Methods: 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.
Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1β secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl−) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl− and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1β secretion.
Conclusions: 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.
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