Unterreiner, Adeline, Rubert, Joelle, Kauffmann, Muriel, Fruhauf, Alice, Heiser, Diane, Erbel, Paulus, Schlapbach, Achim, Eder, Joerg, Bodendorf, Ursula, Boettcher, Andreas, Farady, Christopher and Bornancin, Frederic (2021) Pharmacological inhibition of IKKβ dampens NLRP3 inflammasome activation after priming in the human myeloid cell line THP-1. Biochemical and biophysical research communications : BBRC, 545. pp. 177-182. ISSN 0006291X

Abstract

The NLRP3 inflammasome is a critical component of the innate immune response to sterile inflammation. Its regulation involves a priming step, required for up-regulation of inflammasome protagonists and an activation step leading to NLRP3 inflammasome complex assembly, which triggers caspase-1 activity. The IκKβ kinase regulates canonical NF-κB, a key pathway involved in transcriptional priming. We found that IκKβ also regulates the activation and function of the NLRP3 inflammasome. Two unrelated IκKβ inhibitors, AFN700 and TPCA-1, when applied after priming, fully prevented IL-1β secretion triggered by nigericin in THP-1 cells. Both inhibitors prevented neither inflammasome assembly, as monitored by measuring the formation of ASC specks, nor the generation of caspase-1 p20, a hallmark of caspase-1 activity, but they impaired the initial cleavage and activation of procaspase-1. These data thus indicate that IκKβ activity is required for efficient activation of NLRP3, suggesting that IκKβ may fulfill a dual role in coupling priming and activation of the NLRP3 inflammasome.

Item Type:	Article
Keywords:	NLRP3, IKK, caspase-1
Date Deposited:	27 Apr 2021 00:45
Last Modified:	27 Apr 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44035