Kielian Tammy, Phulwani Nirmal K, Esen Nilufer, Syed Mohsin Md, Haney Anessa C, McCastlain Kelly, Johnson Jennifer
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
J Immunol. 2007 Apr 1;178(7):4528-37. doi: 10.4049/jimmunol.178.7.4528.
Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1beta, TNF-alpha, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-alpha, IL-6, MIP-1alpha/CCL3, and IFN-gamma-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.
脑脓肿是由化脓性细菌引起的实质性感染所形成的，金黄色葡萄球菌是人类疾病的常见病原体。许多参与细菌免疫反应的受体，包括大多数Toll样受体（TLR）、白细胞介素-1受体（IL-1R）和白细胞介素-18受体（IL-18R），都使用一种共同的衔接分子髓样分化因子88（MyD88）来转导激活信号，从而导致促炎介质表达和免疫效应功能。为了阐明MyD88依赖性信号在脑脓肿中的重要性，我们使用MyD88基因敲除（KO）小鼠和野生型（WT）小鼠比较了疾病的发病机制。MyD88基因敲除小鼠的死亡率显著更高，这与包括但不限于白细胞介素-1β、肿瘤坏死因子-α和巨噬细胞炎性蛋白-2/趋化因子配体2（MIP-2/CXCL2）在内的几种促炎介质表达的显著降低相关。这些变化与MyD88基因敲除动物脑脓肿中中性粒细胞和巨噬细胞募集的显著减少有关。此外，与野生型细胞相比，从MyD88基因敲除小鼠的脑脓肿中分离出的小胶质细胞、巨噬细胞和中性粒细胞产生的肿瘤坏死因子-α、白细胞介素-6、巨噬细胞炎性蛋白-1α/趋化因子配体3（MIP-1α/CCL3）和干扰素-γ诱导蛋白10/趋化因子配体10（CXCL10）明显更少。MyD88依赖性信号的缺失对组织损伤程度有显著影响，MyD88基因敲除动物的脑脓肿明显更大，其特征是水肿和坏死加剧。有趣的是，尽管MyD88基因敲除小鼠出现了这些显著变化，但在早期检测时间点，两种品系之间的细菌载量没有显著差异。总体而言，这些发现表明，MyD88在脑脓肿发展的早期阶段建立保护性中枢神经系统宿主反应中起重要作用，而MyD88非依赖性途径负责病原体的控制。
