Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; Neurosciences Graduate Program, Stanford Neurosciences Institute, Stanford University, Stanford, CA 94305;
Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305; BIO5 Institute, University of Arizona, Tucson, AZ 85721;
J Immunol. 2014 Jul 1;193(1):139-49. doi: 10.4049/jimmunol.1303284. Epub 2014 May 23.
The balance between controlling infection and limiting inflammation is particularly precarious in the brain because of its unique vulnerability to the toxic effects of inflammation. Astrocytes have been implicated as key regulators of neuroinflammation in CNS infections, including infection with Toxoplasma gondii, a protozoan parasite that naturally establishes a chronic CNS infection in mice and humans. In CNS toxoplasmosis, astrocytes are critical to controlling parasite growth. They secrete proinflammatory cytokines and physically encircle parasites. However, the molecular mechanisms used by astrocytes to limit neuroinflammation during toxoplasmic encephalitis have not yet been identified. TGF-β signaling in astrocytes is of particular interest because TGF-β is universally upregulated during CNS infection and serves master regulatory and primarily anti-inflammatory functions. We report in this study that TGF-β signaling is activated in astrocytes during toxoplasmic encephalitis and that inhibition of astrocytic TGF-β signaling increases immune cell infiltration, uncouples proinflammatory cytokine and chemokine production from CNS parasite burden, and increases neuronal injury. Remarkably, we show that the effects of inhibiting astrocytic TGF-β signaling are independent of parasite burden and the ability of GFAP(+) astrocytes to physically encircle parasites.
在大脑中，控制感染和限制炎症之间的平衡特别不稳定，因为大脑对炎症的毒性作用特别脆弱。星形胶质细胞被认为是中枢神经系统感染中神经炎症的关键调节因子，包括弓形虫感染，弓形虫是一种原生动物寄生虫，在小鼠和人类中自然建立慢性中枢神经系统感染。在中枢神经系统弓形体病中，星形胶质细胞对于控制寄生虫的生长至关重要。它们分泌促炎细胞因子并将寄生虫包围起来。然而，星形胶质细胞在弓形体脑炎中限制神经炎症的分子机制尚未确定。星形胶质细胞中的 TGF-β 信号通路特别引人关注，因为 TGF-β 在中枢神经系统感染过程中普遍上调，具有主要的调节和抗炎作用。在本研究中，我们报告在弓形体脑炎期间星形胶质细胞中的 TGF-β 信号通路被激活，并且抑制星形胶质细胞的 TGF-β 信号通路增加免疫细胞浸润，使促炎细胞因子和趋化因子的产生与中枢神经系统寄生虫负荷脱耦，并增加神经元损伤。值得注意的是，我们表明抑制星形胶质细胞 TGF-β 信号通路的作用独立于寄生虫负荷和 GFAP(+)星形胶质细胞包围寄生虫的能力。
