Herrero Lara J, Sheng Kuo-Ching, Jian Peng, Taylor Adam, Her Zhisheng, Herring Belinda L, Chow Angela, Leo Yee-Sin, Hickey Michael J, Morand Eric F, Ng Lisa F P, Bucala Richard, Mahalingam Suresh
Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
Arthritis Rheum. 2013 Oct;65(10):2724-36. doi: 10.1002/art.38090.
Arthrogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) circulate worldwide. This virus class causes debilitating illnesses that are characterized by arthritis, arthralgia, and myalgia. In previous studies, we identified macrophage migration inhibitory factor (MIF) as a critical inflammatory factor in the pathogenesis of alphaviral diseases. The present study was undertaken to characterize the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides.
Mouse models of RRV and CHIKV infection were used to investigate the immunopathogenesis of arthritic alphavirus infection. The role of CD74 was assessed using histologic analysis, real-time polymerase chain reaction, flow cytometry, and plaque assay.
In comparison to wild-type mice, CD74-/- mice developed only mild clinical features and had low levels of tissue damage. Leukocyte infiltration, characterized predominantly by inflammatory monocytes and natural killer cells, was substantially reduced in the infected tissue of CD74-/- mice, but production of proinflammatory cytokines and chemokines was not decreased. CD74 deficiency was associated with increased monocyte apoptosis, but had no effect on monocyte migratory capacity. Consistent with these findings, alphaviral infection resulted in a dose-dependent up-regulation of CD74 expression in human peripheral blood mononuclear cells, and serum MIF levels were significantly elevated in patients with RRV or CHIKV infection.
CD74 appears to regulate immune responses to alphaviral infection through its effects on cellular recruitment and survival. These findings suggest that both MIF and CD74 play a critical role in mediating alphaviral disease, and blocking these factors with novel therapeutic agents could substantially ameliorate the pathologic manifestations.
罗斯河病毒（RRV）和基孔肯雅病毒（CHIKV）等致关节炎性甲病毒在全球范围内传播。这类病毒会引发使人衰弱的疾病，其特征为关节炎、关节痛和肌痛。在先前的研究中，我们确定巨噬细胞迁移抑制因子（MIF）是甲病毒疾病发病机制中的关键炎症因子。本研究旨在确定MIF的细胞表面受体CD74在RRV和CHIKV诱导的甲病毒关节炎中的作用。
使用RRV和CHIKV感染的小鼠模型来研究关节炎性甲病毒感染的免疫发病机制。使用组织学分析、实时聚合酶链反应、流式细胞术和蚀斑测定法评估CD74的作用。
与野生型小鼠相比，CD74基因敲除小鼠仅出现轻微的临床症状，组织损伤水平较低。在CD74基因敲除小鼠的感染组织中，以炎性单核细胞和自然杀伤细胞为主的白细胞浸润显著减少，但促炎细胞因子和趋化因子的产生并未减少。CD74缺乏与单核细胞凋亡增加有关，但对单核细胞迁移能力没有影响。与这些发现一致，甲病毒感染导致人外周血单核细胞中CD74表达呈剂量依赖性上调，RRV或CHIKV感染患者的血清MIF水平显著升高。
CD74似乎通过其对细胞募集和存活的影响来调节对甲病毒感染的免疫反应。这些发现表明，MIF和CD74在介导甲病毒疾病中都起着关键作用，用新型治疗药物阻断这些因子可显著改善病理表现。
