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* Department of Immunology and
Department of Parasitology, Institute of Allergy and Immune-Related Diseases,
Laboratories of Neuroscience, and
Allergy and Clinical Immunology, Center for Medical Research, Wuhan University School of Medicine, Wuhan, People’s Republic of China;
¶ The State Key Laboratory of Molecular Biology and Neuroscience, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, People’s Republic of China;
|| The State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, People’s Republic of China;
# Key Laboratory of Colloid, Interface Science and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, People’s Republic of China;
** Department of Immunology, College of Basic Medical Sciences, Anhui Medical University, Hefei, People’s Republic of China;
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; and
* Department of Immunology, Fourth Military Medical University, Xian, People’s Republic of China
What mechanism that determines microglia accomplishing destructive or constructive role in CNS remains nebulous. We report here that intracranial priming and rechallenging with Toxoplasma gondii in mice elicit neurotoxic CCR9+Irg1+ (immunoresponsive gene 1) microglia, which render resistance to apoptosis and produce a high level of TNF-
; priming and rechallenging with lymphocytic choriomeningitis virus elicit neurosupportive CXCR3+Irg1– microglia, which are sensitive to apoptosis and produce a high level of IL-10 and TGF-
. Administration of CCR9 and/or Irg1 small interfering RNA alters the frequency and functional profiles of neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1– microglia in vivo. Moreover, by using a series of different neurotropic pathogens, including intracellular parasites, chronic virus, bacteria, toxic substances, and CNS injury to intracranially prime and subsequent rechallenge mice, the bi-directional elicitation of microglia has been confirmed as neurotoxic CCR9+Irg1+ and neurosupportive CXCR3+Irg1– cells in these mouse models. These data suggest that there exist two different types of microglia, providing with a novel insight into microglial involvement in neurodegenerative and neuroinflammatory pathogenesis such as Alzheimer’s disease and AIDS dementia.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was supported by the National Key Basic Research Program of China from the Ministry of Science and Technology of People’s Republic of China (Grants 2001CB510004 and 2001CB510008), the National Natural Science Foundation of China (Grants 39870674, 30572119, 30030130, and 30471509), a special grant from the Personnel Department of Wuhan University, China, and the Research Foundation of Health Department of Hubei Provincial Government, China (Grant 301140344). T.J. is a Chang Jiang Scholar supported by Chang Jiang Scholars Program from Ministry of Education, People’s Republic of China, and Li Ka Shing Foundation, Hong Kong, People’s Republic of China.
2 H.L., Z.G., H.Y., and X.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Tan Jinquan, Department of Immunology, Wuhan University School of Medicine, Dong Hu Road 115, Wuchang 430071, Wuhan, People’s Republic of China. E-mail address: jinquan_tan{at}hotmail.com
4 Abbreviations used in this paper: Irg1, immunoresponsive gene 1; STAg, soluble tachyzoite Ag; rLCMVNP, recombinant nucleoprotein immunodominant domain of lymphocytic choriomeningitis virus; siRNA, small interfering RNA.
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