Different neurotropic pathogens elicit neurotoxic CCR9- or neurosupportive CXCR3-expressing microglia.
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-alpha; 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-beta. 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.
Li
He
H
Department of Immunology, Institute of Allergy and Immune-Related Diseases, Center for Medical Research, Wuhan University School of Medicine, Wuhan's People's Republic of China.
Gang
Zhou
Z
Yuling
He
H
Luokun
Xie
X
Jie
Xiong
X
Hao
Lei
L
Li
Wei
W
Chunsong
Hu
H
Junyan
Liu
L
Mingshen
Jiang
J
Youxin
Jin
J
Feili
Gong
G
Boquan
Jin
J
Jinquan
Tan
T
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000469:parasitology* / Q000473:pathology / Q000821:virology*; D009498:Neurotoxins / Q000096:biosynthesis* / Q000235:genetics / Q000633:toxicity*; D054388:Receptors, CCR; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity*; D014123:Toxoplasmosis / Q000276:immunology / Q000378:metabolism / Q000469:parasitology
C119309:CC chemokine receptor 9; C515188:Cxcr3 protein, mouse; D009498:Neurotoxins; D054388:Receptors, CCR; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine