Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis
Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis
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DOI：
10.1164/rccm.202106-1426oc
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发表时间：
2022-04-01
影响因子：
24.7
通讯作者：
Reeves, Emer P.
中科院分区：
文献类型：
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作者：
Gabillard-Lefort, Claudie;Casey, Michelle;Reeves, Emer P.
基本原理：囊性纤维化（CF）是由CFTR（CF跨膜传导调节因子）基因突变引起的，其特征在于持续的炎症。ATP通过P2 X7 R触发IL-1 β分泌（P2 X7受体）和NLRP 3的激活目的：探讨CFTR调节剂elexacaftor/tezacaftor/ivacaftor对炎性小体（NOD-、LRR-和pyrin domain containing protein 3）的影响。（Trikafta）对CFTR表达和单核细胞中ATP/P2 X7 R信号传导轴以及循环促炎标志物的影响。在Trikafta治疗前和治疗3个月后，在42例CF患者的血液中检测了炎症介质。在有或没有P2 X7 R抑制剂A438079的情况下，在用ATP和LPS刺激之前和之后测量单核细胞中炎性体活化和IL-1 β分泌的标志物。测量和主要结果：P2 X7 R在CF单核细胞中过表达，并且受体抑制降低NLRP 3表达、半胱天冬酶-1活化和IL-1 β分泌。在体外和体内，P2 X7 R的表达受CFTR功能和细胞内氯离子（Cl-）水平的调节。Trikafta治疗恢复了CF单核细胞中的CFTR表达，但降低了P2 X7 R，导致Cl-和钾流出正常化，并降低了细胞内钙水平。CFTR调节剂治疗降低了ATP和LPS的循环水平，减少了炎性小体活化和IL-1b分泌。结论：P2 X7 R的表达受细胞内Cl-水平的调节，CF单核细胞促进炎性小体活化。Trikafta治疗显著增加CFTR蛋白表达并减少ATP/P2 X7 R诱导的炎性小体活化。因此，P2 X7 R可能是一个有希望的靶点，用于减少不适合Trikafta或其他CFTR调节剂治疗的CF患者的炎症。
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-1 beta 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-1 beta 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-1 beta 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-1b 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.