More than 2 million Americans suffer from lupus, a widespread and life-long autoimmune disease. The detrimental role of B lymphocytes in lupus is evidenced by high levels of pathogenic antinuclear autoantibodies (ANAs) found in the patients. Suppression of autoantibody production by B cells has been considered as a therapeutic strategy for lupus. In addition, myeloid cells, in particular macrophages and neutrophils, contribute significantly to lupus development and lupus progression by producing pro-inflammatory cytokines and chemoattractant factors. Either blocking myeloid cell trafficking or suppressing their ability in producing inflammatory cytokines can reduce the clinical symptoms of lupus in both animal models and human patients. We have shown that inositol-requiring enzyme 1 alpha (IRE1?), the primary Unfolded Protein Response (UPR) transducer, is required for B cell differentiation into plasma cells. More recently, we discovered that inhibition of IRE1? suppressed inflammatory cytokine production by macrophages and neutrophils and protected mice from inflammatory arthritis. Further, we have obtained provocative preliminary evidence that the IRE1?-mediated UPR pathway is elevated in the peripheral leukocytes from lupus patients. Through both genetic and pharmacological approaches, we found that IRE1? is required for B cell differentiation into plasma and autoantibody production in the Lupus animal model, suggesting that IRE1? represents a unique, high-efficient therapeutic target for lupus. Additionally, we have identified a specific, non-toxic IRE1? inhibitor, 4?8c, which can efficiently suppress antibody production by B cells and pro-inflammatory cytokine production by macrophages and neutrophils. Based on our recent discoveries and preliminary studies, we propose that suppression of IRE1? can repress production of both auto-antibodies by plasma cells and pro-inflammatory cytokines by macrophage/neutrophil and thus protect from the development of lupus. The current proposed study is to use both genetic and pharmacological approaches to evaluation the pre-clinical therapeutic efficacy of IRE1? suppression in lupus treatment (Aim 1) and to delineate the underlying molecular mechanisms of IRE1? in promoting autoantibody production by B cells (Aim 2) and pro-inflammatory cytokine production by myeloid cells (Aim 3) during lupus development. The proposed studies will not only demonstrate a novel therapeutic strategy and a potential drug for lupus, but will also contribute to a better understanding of the molecular basis underlying autoimmune responses associated with auto-antibodies and pro-inflammatory cytokines.
The proposed studies will discover novel molecular mechanisms underlying IRE1a in regulating B cell and macrophage autoimmune response and provide a proof-of-principle evaluation of both genetic and pharmacological IRE1a inhibition in lupus treatment. We believe that our studies will potentially open a door for a new therapy to combat lupus.
|Dandekar, Aditya; Qiu, Yining; Kim, Hyunbae et al. (2016) Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin. J Biol Chem 291:23149-23158|
|Sun, Shengyi; Shi, Guojun; Sha, Haibo et al. (2015) IRE1Î± is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat Cell Biol 17:1546-55|
|Li, Fei; Gao, Beixue; Dong, Hongxin et al. (2015) Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis. PLoS One 10:e0119955|
|Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086|
|Lin, Zhenghong; Tan, Can; Qiu, Quan et al. (2015) Ubiquitin-specific protease 22 is a deubiquitinase of CCNB1. Cell Discov 1:|
|Zhang, Xuebao; Cai, Juan; Zheng, Ze et al. (2015) A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression. Cell Discov 1:15024|
|Kong, Sinyi; Thiruppathi, Muthusamy; Qiu, Quan et al. (2014) DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-ÎºB transcriptional activity. J Immunol 193:5515-24|
|Yang, Heeyoung; Qiu, Quan; Gao, Beixue et al. (2014) Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. J Exp Med 211:2467-79|