de Paula Souza, Joyce, Jeanneau, Karine, Allard, Cyril, Angevaare, Eline, Aschenbrenner, Dominik, Bassi, Zuni, Bodendorf, Ursula, Demarco, Benjamin, Farady, Christopher, Gounarides, John, Killmer, Saskia, Kovarik, Jiri, Pfister, Sabina, Yin, Hong2, Hepprich, Matthias, Fischer, Justus S., Ratnarasa, Vithushan, Böni-Schnetzler, Marianne, Meier, Daniel T., Wieczorek, Grazyna and Donath, Marc Y. NLRP3 and caspase-1 inhibitors block NLRP3 inflammasome activity in peripheral blood monocytes of T2D patients and healthy controls.

Abstract

Type-2 Diabetes (T2D), a metabolic disorder characterized by hyperglycaemia and dyslipidemia, is associated with several clinical complications. Several studies underscore the presence of chronic systemic inflammation in T2D patients, which is related to the development of obesity, disease progression, and micro- and macrovascular complications. In this study, we conduct a comparative analysis of clinical parameters, free fatty acid profiles, immune cell subsets, and inflammatory responses of peripheral blood mononuclear cells (PBMCs) obtained from both healthy individuals and those diagnosed with T2D. Free fatty acid plasma profiling revealed dysregulation in T2D subjects, indicating potential modulation of immune cell responses by lipids. Moreover, mild systemic inflammation was observed in T2D patients, with elevated serum levels of inflammatory cytokines ASC, IL-1RA, and IL-18BPa. Functional assessments further demonstrated comparable NLRP3 inflammasome activity in PBMCs from both groups, suggesting that systemic inflammation in T2D may be driven more by elevated leucocyte numbers than by inherent proinflammatory profiles. Treatment with NLRP3 and caspase-1 inhibitors successfully suppressed release of pro-inflammatory cytokines ex-vivo. Therefore inhibition of inflammasome activation emerges as a promising therapeutic strategy for management of diabetes-related complications.

Item Type:	Article
Keywords:	NLRP3, CASP-1, NEK7, IL-1b, IL-18, T2D
Date Deposited:	28 Sep 2024 00:45
Last Modified:	28 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54617