INHIBITORS OF BRUTON’S TYROSINE KINASE ALTER NF-κB AND NLRP3 INFLAMMATION IN MACROPHAGES

Abstract

Obesity-related inflammation increases one’s risk of developing cardiovascular disease, type 2 diabetes, among many other disorders. Energy imbalance during obesity overwhelms the adipose tissue leading to immune cell infiltration, elevations in pro-inflammatory cytokines, and consequent local and systemic insulin resistance. Certain potent pro-inflammatory cytokines are produced by the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This metabolic danger sensor is involved in a variety of autoimmune and inflammatory conditions, hence regulation of this node as a therapeutic approach is a topic of great interest. To date, there is no clinically approved inhibitor of the inflammasome, which makes indirect targeting through endogenous molecules an attractive area of research. Bruton’s tyrosine kinase has been shown to physically interact with NLRP3 inflammasome components and is required for its production of pro-inflammatory cytokine, IL-1β. However, the consequences of BTK inhibition on metabolic tissues like adipose tissue remain largely unstudied. In vitro experiments showed that pharmacological BTK inhibitors lower NLRP3 inflammasome priming and activation in macrophages. Bone marrow-derived macrophages (BMDMs) from a Btk-null mice strain treated with BTK inhibitors demonstrated lowering of lipopolysaccharide (LPS) -induced elevations in inflammatory cytokines. This effect was interestingly observed in both BMDMs derived from wild-type and Btk-null mice, postulating the idea that pharmacological inhibitors of BTK have anti-inflammatory properties that do not require the presence of the BTK gene product. Further, the optimized conditions for testing the influence of BTK inhibitors on adipose tissue insulin signaling ex vivo is outlined. Future work should focus on pinpointing off-targets shared between BTK inhibitors to identify the node responsible for the observed anti-inflammatory effects. This research may lead to the development of an alternative therapeutic approach to treating inflammatory and autoimmune diseases mediated by the NLRP3 inflammasome.