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.
|Wang, Jie-Mei; Qiu, Yining; Yang, Zhao et al. (2018) IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11:|
|Hou, Xia; Yang, Zhao; Zhang, Kezhong et al. (2017) SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6. Biochem Biophys Res Commun 494:446-451|
|Yang, Zhao; Kim, Hyunbae; Ali, Arushana et al. (2017) Interaction between stress responses and circadian metabolism in metabolic disease. Liver Res 1:156-162|
|Huang, Anfei; Yang, Yi; Chen, Si et al. (2017) MiR-34a promotes DCs development and inhibits their function on T cell activation by targeting WNT1. Oncotarget 8:17191-17201|
|Dominguez, Donye; Ye, Cong; Geng, Zhe et al. (2017) Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer. J Immunol 198:1365-1375|
|Wang, Yajun; Yun, Chawon; Gao, Beixue et al. (2017) The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. Cell Rep 20:600-612|
|Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938|
|Kong, Sinyi; Yang, Yi; Xu, Yuanming et al. (2016) Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proc Natl Acad Sci U S A 113:10394-9|
|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|
|Xu, Yuanming; Zhao, Fang; Qiu, Quan et al. (2016) The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat Commun 7:12073|
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