Impaired microglial activation in the brain of IL-18-gene-disrupted mice after neurovirulent influenza A virus infection.
Knockout of the interleukin-18 (IL-18) gene predisposed mice to impaired clearance of neurovirulent influenza A virus-infected neurons from the brain. In wild-type mice, IL-18 molecule-producing microglia/macrophages emerged in virally attacked regions as early as day 3 after infection. Microglial transformation into macrophages culminated at day 7 to 9, with upregulated expression of Iba1, a novel calcium-binding protein that controls phagocytic functions of microglia/macrophages. In IL-18-/- mice, microglial transformation was interrupted with reduced Iba1 expression. Interferon-gamma (IFN-gamma)-immunopositive neurons appeared in and around virally invaded regions in wild-type mice, peaking in number at day 7, whereas such cells were barely detected in IL-18-/- mice. Stereotaxic microinjection of recombinant IFN-gamma triggered microglial transformation in IL-18-/- mice and upregulated Iba1 expression, leading to effective eradication of virally infected neurons. Collectively, these results suggest that IL-18 plays a key role in activating microglial functions directed against the influenza virus infection by inducing neuronal IFN-gamma in the brain parenchyma.
Mori
I
I
Department of Microbiology, Fukui Medical University School of Medicine, Fukui, Japan.
Hossain
M J
MJ
Takeda
K
K
Okamura
H
H
Imai
Y
Y
Kohsaka
S
S
Kimura
Y
Y
D000818:Animals; D001921:Brain / Q000503:physiopathology* / Q000821:virology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D009980:Influenza A virus; D007371:Interferon-gamma / Q000494:pharmacology; D020382:Interleukin-18 / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D017628:Microglia / Q000502:physiology* / Q000821:virology; D008845:Microinjections; D009976:Orthomyxoviridae Infections / Q000503:physiopathology*; D013047:Specific Pathogen-Free Organisms; D015854:Up-Regulation / Q000187:drug effects
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D020382:Interleukin-18; D008840:Microfilament Proteins; D007371:Interferon-gamma