The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells.

The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells. Sci Signal. 2020 Jun 02;13(634): Authors: Corzo CA, Varfolomeev E, Setiadi AF, Francis R, Klabunde S, Senger K, Sujatha-Bhaskar S, Drobnick J, Do S, Suto E, Huang Z, Eastham-Anderson J, Katewa A, Pang J, Domeyer M, Dela Cruz C, Paler-Martinez A, Lau VWC, Hadadianpour A, Ramirez-Carrozi V, Sun Y, Bao K, Xu D, Hunley E, Brightbill HD, Warming S, Roose-Girma M, Wong A, Tam L, Emson CL, Crawford JJ, Young WB, Pappu R, McKenzie BS, Asghari V, Vucic D, Hackney JA, Austin CD, Lee WP, Lekkerkerker A, Ghilardi N, Bryan MC, Kiefer JR, Townsend MJ, Zarrin AA Abstract The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research