Impaired Microglial Activation in the Brain of IL-18-Gene-Disrupted Mice after Neurovirulent Influenza A Virus Infection

Abstract

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.

Interleukin-18

“…In an in vivo model of vaccinia infection, IL-18 administration reduces pock formation [109]. Clearance of neurovirulent influenza A-infected neurons by microglial/ macrophage cells is impaired in the brains of IL-18-deficient mice [98]. Down-modulation of IL-18-induced immune responses by human papilloma virus (HPV) oncoproteins may contribute to viral pathogenesis or carcinogenesis.…”

Vaccinia Virus Interleukin-18-Binding Protein Promotes Virulence by Reducing Gamma Interferon Production and Natural Killer and T-Cell Activity

“…Ϫ/Ϫ mice demonstrated a role in protection against herpes simplex virus type 2 (HSV-2) infection (22) and in modulation of the IFN-␥ response to infection with adenovirus (62), murine cytomegalovirus (CMV) (41), and influenza virus (36). Administration of IL-18 also protected mice from acute infection with HSV-1 (19) and encephalomyocarditis virus (26,57).…”

Loss of microglial ramification in microglia‐astrocyte cocultures: Involvement of adenylate cyclase, calcium, phosphatase, and Gi‐protein systems

“…Deletion or overexpression of MCSF, IL6, or systemic application of LPS all change the level of microglial activation but do not affect transformation into macrophages (Fattori et al, 1995;Galiano et al, 2002;Kalla et al, 2001;Kloss et al, 2001). Deletion of IL18 in neuroviral infection (Mori et al, 2001) and TGF␤1 or both TNF receptors in facial axotomy (Raivich et al, 2002;Rong et al, 2001) prevents the appearance of ameboid macrophages, but the effect seems to be indirect, due to the inhibition of cell death and the appearance of cell debris.…”