title: Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis.
abstract: Microbial infections of the central nervous system (CNS) are often associated with local accumulation of antibody (Ab)-secreting cells (ASC). By providing a source of Ab at the site of infection, CNS-localized ASC play a critical role in acute viral control and in preventing viral recrudescence. Following coronavirus-induced encephalomyelitis, the CNS accumulation of ASC is chemokine (C-X-C motif) receptor 3 (CXCR3) dependent. This study demonstrates that CNS-expressed CXCR3 ligand CXCL10 is the critical chemokine regulating ASC accumulation. Impaired ASC recruitment in CXCL10(-/-) but not CXCL9(-/-) mice was consistent with reduced CNS IgG and κ-light chain mRNA and virus-specific Ab. Moreover, the few ASC recruited to the CNS in CXCL10(-/-) mice were confined to the vasculature, distinct from the parenchymal localization in wild-type and CXCL9(-/-) mice. However, neither CXCL9 nor CXCL10 deficiency diminished neutralizing serum Ab, supporting a direct role for CXCL10 in ASC migration. T cell accumulation, localization, and effector functions were also not affected in either CXCL9(-/-) or CXCL10(-/-) mice, consistent with similar control of infectious virus. There was also no evidence for dysregulation of chemokines or cytokines involved in ASC regulation. The distinct roles of CXCL9 and CXCL10 in ASC accumulation rather coincided with their differential localization. While CXCL10 was predominantly expressed by astrocytes, CXCL9 expression was confined to the vasculature/perivascular spaces. These results suggest that CXCL10 is critical for two phases: recruitment of ASC to the CNS vasculature and ASC entry into the CNS parenchyma.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D017934:Coronavirus / Q000276:immunology* / Q000472:pathogenicity; D018352:Coronavirus Infections / Q000276:immunology* / Q000821:virology; D004679:Encephalomyelitis / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse