Role of Type I Interferons in a Self-Sustaining Murine Model of Myositis

I 型干扰素在肌炎自我维持小鼠模型中的作用

• 批准号: 7356623
• 负责人: THOMAS A GRIFFIN
• 金额: $ 16.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356623
• 关键词: Affect; Breeding; Chronic; Chronic Disease; Class; Condition; Connective Tissue Diseases; Dermatomyositis; Development; Disease; Goals; Histocompatibility Antigens Class I; Human; Idiopathic Inflammatory Myopathies; Immune; Inclusion Body Myositis; Inflammation; Injury; Interferon Type I; Interferons; MHC Class I Genes; Maintenance; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Myositis; Nature; Production; Proteins; Role; Skeletal Muscle; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Week; Work; in vivo; mouse model; novel; protein folding; response; type I interferon receptor

DESCRIPTION (provided by applicant): Idiopathic inflammatory myopathies comprise a group of connective tissue diseases that include dermatomyositis, polymyositis, and inclusion body myositis. Each of these conditions is characterized by chronic skeletal muscle inflammation and muscle fiber damage. Demonstration of persistent excessive expression of MHC class I molecules and an associated unfolded protein response (UPR) in affected muscle fibers in each of these conditions suggests a common mechanism for chronic muscle fiber injury. A central pathogenic role for MHC class I is indicated by a mouse model, in which chronic myositis is induced by conditional expression of a transgenic MHC class I molecule, H-2Kb, specifically in skeletal muscle fibers, which typically express very little endogenous MHC class I. Transgenic H-2Kb expression overwhelms the protein folding system of muscle fibers and activates an UPR, which appears to mimic what occurs in human myositis. Remarkably, several weeks of transgenic H-2Kb expression is all that is needed to induce self-sustaining myositis that is driven by increased expression of endogenous MHC class I molecules in muscle fibers, which persists long after transgenic H-2Kb expression is suppressed. The mechanism for induction and maintenance of endogenous MHC class I expression is unclear, though we theorize that type I interferons are involved, since they are potent inducers of MHC class I expression, and there is evidence for type I interferon action in affected muscle tissue in both mouse and human myositis. Additionally, we have recently discovered that the UPR can strongly enhance expression of type I interferons, particularly in the context of concurrent innate immune activation. This finding suggests a novel connection between the MHC class I-induced UPR and MHC class I-inducing type I interferons that leads us to hypothesize that UPR-induced type I interferons are produced by affected skeletal muscle fibers and are critical mediators of sustained endogenous MHC class I expression in the murine model of myositis. We will test this hypothesis by characterizing type I interferon production in muscle cells and tissue in response to excessive MHC class I expression and UPR activation, and by determining the role of type I interferon action in the mouse model of myositis by assessing the impact of type I interferon receptor deficiency. Ultimately, elucidating the mechanism of chronic myositis in the mouse model should make important contributions to understanding the mechanism of chronic human myositis, and provide strong rationale for development of novel treatments for human myositis that disrupt the proposed self-sustaining cycle of chronic disease.

描述(申请人提供)：特发性炎症性肌病包括一组结缔组织疾病，包括皮肌炎、多发性肌炎和包涵体肌炎。每一种情况都以慢性骨骼肌炎症和肌肉纤维损伤为特征。在这些情况下，MHC-I类分子的持续过度表达和相关的未折叠蛋白反应(UPR)在每种情况下都表明了慢性肌肉纤维损伤的共同机制。小鼠模型表明了MHC I类分子的中心致病作用，在该模型中，转基因MHC I类分子H-2kb的有条件表达诱导了慢性肌炎，这种表达通常在骨骼肌纤维中表达很少的内源性MHC I类分子，转基因H-2kb的表达压倒了肌肉纤维的蛋白质折叠系统并激活了UPR，这似乎模拟了人类肌炎发生的情况。值得注意的是，几周的转基因H-2kb表达就是诱导自持性肌炎所需的全部，这是由肌肉纤维中内源性MHC I类分子表达增加所驱动的，在转基因H-2kb表达被抑制后持续很长时间。诱导和维持内源性MHC I类表达的机制尚不清楚，尽管我们推测I型干扰素参与了MHC I类表达，因为它们是MHC I类表达的有力诱导者，而且有证据表明I型干扰素在小鼠和人类肌炎受影响的肌肉组织中起作用。此外，我们最近发现，UPR可以强烈地增强I型干扰素的表达，特别是在同时存在天然免疫激活的情况下。这一发现表明，MHC I类诱导的UPR和MHC I类诱导的I型干扰素之间存在新的联系，这导致我们假设UPR诱导的I型干扰素是由受影响的骨骼肌纤维产生的，是肌炎小鼠模型中持续内源性MHC I类表达的关键介质。我们将通过表征肌肉细胞和组织中因MHC-I类过度表达和UPR激活而产生的I型干扰素来验证这一假设，并通过评估I型干扰素受体缺陷的影响来确定I型干扰素在肌炎小鼠模型中的作用。最终，在小鼠模型中阐明慢性肌炎的机制将为理解慢性人类肌炎的机制做出重要贡献，并为开发新的治疗人类肌炎的方法提供强有力的理论基础，从而扰乱慢性疾病的自我维持周期。