作者
Cesar A. Corzo,Eugene Varfolomeev,Audi Setiadi,Ross Francis,Sha Klabunde,Kate Senger,Swathi Sujatha-Bhaskar,Joy Drobnick,Steven Do,Eric Suto,Zhiyu Huang,Jeffrey Eastham‐Anderson,Arna Katewa,Jodie Pang,Melanie Domeyer,Christopher Dela Cruz,Andrés Paler-Martı́nez,Vivian Wing Chong Lau,Azadeh Hadadianpour,Vladimir Ramirez-Carrozzi,Yonglian Sun,Katherine Bao,Daqi Xu,Emily Hunley,Hans D. Brightbill,Søren Warming,Merone Roose‐Girma,Alfred Wong,Lucinda Tam,Claire Emson,James J. Crawford,Xiaojing Wang,Rajita Pappu,Brent S. McKenzie,Vida Asghari,Domagoj Vucic,Jason A. Hackney,Cary D. Austin,Wyne P. Lee,Annemarie Lekkerkerker,Nico Ghilardi,Marian C. Bryan,James R. Kiefer,Michael J. Townsend,Ali A. Zarrin
摘要
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.