A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo

• Published in: European journal of pharmacology Vol. 944; p. 175593
• Main Authors: Choudhary, Saynaz A., Patra, Debarun, Sinha, Archana, Mazumder, Sayani, Pant, Rajat, Chouhan, Raju, Jha, Anupam Nath, Prusty, Biswa Mohan, Manna, Debasis, Das, Sajal K., Tikoo, Kulbhushan, Pal, Durba, Dasgupta, Suman
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.04.2023
• Subjects: Animals; Inflammation; Inflammation - metabolism; Interleukin-1 Receptor-Associated Kinases - metabolism; IRAK4 inhibitor; Lipopolysaccharides - metabolism; Macrophages; Macrophages - metabolism; Mice; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; Toll-Like Receptor 4 - metabolism; Toll-like receptor 4 signaling; Vanillin; CD; NF-κB; AP1; IRF3; TRAF6; IRAK4 inhibitor; Inflammation; MD2; Vanillin; Toll-like receptor 4 signaling; Macrophages
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175593

Increasing evidence supports vanillin and its analogs as potent toll-like receptor signaling inhibitors that strongly attenuate inflammation, though, the underlying molecular mechanism remains elusive. Here, we report that vanillin inhibits lipopolysaccharide (LPS)-induced toll-like receptor 4 activation in macrophages by targeting the myeloid differentiation primary-response gene 88 (MyD88)-dependent pathway through direct interaction and suppression of interleukin-1 receptor-associated kinase 4 (IRAK4) activity. Moreover, incubation of vanillin in cells expressing constitutively active forms of different toll-like receptor 4 signaling molecules revealed that vanillin could only able to block the ligand-independent constitutively activated IRAK4/1 or its upstream molecules-associated NF-κB activation and NF-κB transactivation along with the expression of various proinflammatory cytokines. A significant inhibition of LPS-induced IRAK4/MyD88, IRAK4/IRAK1, and IRAK1/TRAF6 association was evinced in response to vanillin treatment. Furthermore, mutations at Tyr262 and Asp329 residues in IRAK4 or modifications of 3-OMe and 4-OH side groups in vanillin, significantly reduced IRAK4 activity and vanillin function, respectively. Mice pretreated with vanillin followed by LPS challenge markedly impaired LPS-induced IRAK4 activation and inflammation in peritoneal macrophages. Thus, the present study posits vanillin as a novel and potent IRAK4 inhibitor and thus providing an opportunity for its therapeutic application in managing various inflammatory diseases. [Display omitted] •Vanilin acts as a potent bispecific inhibitor of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4).•Vanilin reduces TLR4-dependent inflammation by myddosome disassembly and IRAK4 kinase inhibition.•Modifications at 3-OMe and 4-OH side-groups in vanillin notably altered its activity.•In-vivo application of vanillin prevents LPS-induced IRAK4 activation and inflammation.