1. The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells
- Author
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Lucinda Tam, Annemarie Lekkerkerker, Jeffrey Eastham-Anderson, Melanie Domeyer, Brent S. McKenzie, Azadeh Hadadianpour, Eugene Varfolomeev, Arna Katewa, Steven Do, A. Francesca Setiadi, Wyne P. Lee, Joy Drobnick, Andres Paler-Martinez, Rajita Pappu, Katherine Bao, Marian C. Bryan, Alfred Wong, James J. Crawford, Cesar A. Corzo, Vida Asghari, Sha Klabunde, Vladimir Ramirez-Carrozi, Jodie Pang, Jason A. Hackney, Hans Brightbill, Christopher Dela Cruz, Ross Francis, Yonglian Sun, Merone Roose-Girma, Claire Emson, Wendy B. Young, Michael J. Townsend, James R. Kiefer, Cary D. Austin, Swathi Sujatha-Bhaskar, Emily Hunley, Nico Ghilardi, Daqi Xu, Søren Warming, Kate Senger, Zhiyu Huang, Vivian W. C. Lau, Domagoj Vucic, Ali A. Zarrin, and Eric Suto
- Subjects
Plasma Cells ,Endosomes ,Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,immune system diseases ,Interferon ,medicine ,Agammaglobulinaemia Tyrosine Kinase ,Bruton's tyrosine kinase ,Animals ,Humans ,Kinase activity ,Molecular Biology ,IRGs ,030304 developmental biology ,0303 health sciences ,Membrane Glycoproteins ,biology ,Chemistry ,Cell Biology ,Dendritic Cells ,IRAK4 ,Immune complex ,Cell biology ,Interleukin-1 Receptor-Associated Kinases ,Toll-Like Receptor 7 ,biology.protein ,Signal transduction ,Tyrosine kinase ,030215 immunology ,medicine.drug ,Signal Transduction - 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-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.
- Published
- 2020