Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN‐γ but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro

Abstract

The chemokines CXCL9 and CXCL10 bind to the common receptor CXCR3 and are implicated in the pathogenesis of T-cell-mediated immunity in the central nervous system (CNS). Here we examined the temporal and spatial regulation of the Cxcl9 and Cxcl10 genes in the CNS of mice with myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and by glial cells in vitro. During peak disease the levels of CXCL9 and CXCL10 mRNA and protein were increased significantly in the cerebellum and spinal cord but were reduced during the recovery phase. Expression of these genes in the CNS was abolished in IFN-gamma-receptor deficient mice with MOG-EAE. In wild-type mice, CXCL9 RNA was localized mainly to infiltrating mononuclear cells including lesion and perilesional microglia, while CXCL10 RNA was seen primarily in more distal astrocytes that surrounded the inflammatory lesions. Examination of cultured glia following treatment with IFN-gamma revealed that while both CXCL9 and CXCL10 mRNA transcripts were induced in microglia, only CXCL10 mRNA was induced in astrocytes. Thus, although IFN-gamma is the pivotal mediator of both Cxcl10 and Cxcl9 gene expression in EAE, this cytokine differentially regulates the expression of these genes by astrocytes and microglia. The differential glial localization of these chemokines in EAE suggests CXCL9 and CXCL10 have specialized functions.

Unaltered Neurological Disease and Mortality in CXCR3-Deficient Mice Infected Intracranially with Lymphocytic Choriomeningitis Virus-Armstrong

“…The dependence of the induction of cerebral Cxcl9 gene expression on IFN-␥ during LCM has not been described previously. IFN-␥ is also the primary mediator of Cxcl9 gene expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE) (7). In contrast to the Cxcl9 gene, both IFN-␥-dependent and -independent pathways mediate expression of the Cxcl10 gene in LCM.…”

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

“…CXCR3 can be differentially activated by CXCL9, CXCL10, and CXCL11 (21,30). IFN-γ and TNF-α are major inducers and regulators of both CXCR3 and CXCR3 ligands (31)(32)(33)(34)(35).…”

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…The CXC chemokine ligand 10 (CXCL10) is thought to play an important role in neuroinflammatory diseases and its action may involve neuronal cells (van Marle et al, 2004). During CNS neuroinflammation expression of CXCL10 is elevated several fold (Franciotta et al, 2001;Kieseier et al, 2002;Kolb et al, 1999;Letendre et al, 1999;Sorensen et al, 1999;Xia et al, 2000) and occurs in a variety of CNS cells including astrocytes, microglia, and neurons (Asensio and Campbell, 1999;Carter et al, 2007;Kutsch et al, 2000;Ransohoff et al, 1993;Rossi and Zlotnik, 2000;Shen et al, 2006;Simpson et al, 2000;Wang et al, 1998).…”