Simultaneous Targeting of IRE1a in B Cells and Macrophages for Lupus Therapy

描述(由申请者提供)：超过200万美国人患有狼疮，这是一种广泛存在的终身自身免疫性疾病。在狼疮患者中发现高水平的致病性抗核自身抗体(ANA)，证明了B淋巴细胞在狼疮中的有害作用。抑制B细胞自身抗体的产生被认为是狼疮的一种治疗策略。此外，髓系细胞，特别是巨噬细胞和中性粒细胞，通过产生促炎细胞因子和趋化因子，在狼疮的发展和进展中起着重要作用。无论是阻断髓系细胞的运输，还是抑制其产生炎性细胞因子的能力，都可以减少动物模型和人类患者的狼疮临床症状。我们已经证明，α(肌醇需要酶1α)是B细胞分化为浆细胞所必需的主要的未折叠蛋白反应(UPR)转导途径。最近，我们发现抑制IRE1α可以抑制巨噬细胞和中性粒细胞产生炎性细胞因子，并保护小鼠免受炎症性关节炎的侵袭。此外，我们已经获得了具有挑衅性的初步证据，表明狼疮患者外周血白细胞中IRE1UPR介导的UPR途径升高。通过遗传学和药理学方法，我们发现在狼疮动物模型中，IRE1α是B细胞分化为血浆和产生自身抗体所必需的，这表明IRE1α是一种独特的、高效的狼疮治疗靶点。此外，我们还鉴定了一种特异的、无毒的ire1α抑制剂4μ8c，它可以有效地 抑制B细胞产生抗体以及巨噬细胞和中性粒细胞产生促炎细胞因子。根据我们最近的发现和初步研究，我们认为抑制IRE1α可以抑制浆细胞产生自身抗体和巨噬细胞/中性粒细胞产生促炎细胞因子，从而防止狼疮的发生。本研究拟从遗传学和药理学两方面评价IRE1α抑制在狼疮治疗中的临床前疗效(AIM 1)，并阐明IRE1α在狼疮发病过程中促进B细胞产生自身抗体(AIM 2)和促进髓系细胞产生促炎细胞因子(AIM 3)的潜在分子机制。拟议的研究不仅将展示一种新的治疗策略和治疗狼疮的潜在药物，而且还将有助于更好地了解与自身抗体和促炎细胞因子相关的自身免疫反应的分子基础。

DESCRIPTION (provided by applicant): 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 IRE1α (inositol-requiring enzyme 1α), the primary Unfolded Protein Response (UPR) transducer, is required for B cell differentiation into plasma cells. More recently, we discovered that inhibition of IRE1α suppressed inflammatory cytokine production by macrophages and neutrophils and protected mice from inflammatory arthritis. Further, we have obtained provocative preliminary evidence that the IRE1α-mediated UPR pathway is elevated in the peripheral leukocytes from lupus patients. Through both genetic and pharmacological approaches, we found that IRE1α is required for B cell differentiation into plasma and autoantibody production in the Lupus animal model, suggesting that IRE1α represents a unique, high-efficient therapeutic target for lupus. Additionally, we have identified a specific, non-toxic IRE1α inhibitor, 4μ8c, 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 IRE1α 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 IRE1α suppression in lupus treatment (Aim 1) and to delineate the underlying molecular mechanisms of IRE1α 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.