Pro-inflammatory functions of astrocytes correlate with viral clearance and strain-dependent protection from TMEV-induced demyelinating disease

Abstract

Intracerebral infection of susceptible strains of mice, e.g. SJL/J, with Theiler's murine encephalomyelitis virus (TMEV) leads to a persistent CNS infection accompanied by development of a chronic-progressive inflammatory CNS autoimmune demyelinating disease which is clinically and pathologically similar to human multiple sclerosis. In contrast, resistant strains of mice, e.g. C57BL/6 (B6), effectively clear TMEV from the CNS and do not develop demyelinating disease. Although CD8(+) T cells are crucial for viral clearance in B6 mice, SJL mice also mount potent CD8(+) T cell responses against virus, thus the reason for the viral persistence in the CNS in these mice is unclear. Here, we examined innate anti-viral responses of CNS-resident astrocytes as a potential determinant of viral persistence and disease susceptibility. We demonstrate that B6 astrocytes produce significantly higher levels of cytokines, chemokines and adhesion molecules in response to TMEV infection, or stimulation with IFN-gamma and TNF-alpha or poly I:C than SJL mice. In addition, TMEV more effectively induces MHC I molecules on B6 astrocytes than SJL, corresponding with an increased ability to activate TMEV-specific CD8(+) T cells directly ex vivo. These results suggest that enhanced anti-viral responses of B6 astrocytes contribute to the ability of these mice to clear TMEV from the CNS and therefore to their resistance to the development of autoimmune demyelinating disease.

Development of Postinfection Epilepsy After Theiler's Virus Infection of C57BL/6 Mice

“…This occurrence may be related to underlying processes such as viral propagation and/or accompanying inflammatory responses. Studies in TMEV-infected astrocyte cultures show that at 3 dpi, infected B6 astrocytes produce significantly increased levels of cytokines, chemokines and cell adhesion molecules, including interleukin-6 and tumor necrosis factor (TNF) (18). Transgenic mice with chronic interleukin-6 production develop hippocampal neurodegeneration, hyperexcitability and spontaneous seizures (19).…”

Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade

“…It is also becoming increasingly evident that the resident cells of the CNS are not merely passive bystanders during the local inflammatory process, but may actively participate in the host response to certain viral infections of the CNS (46,47). Thus, in the case of i.c.…”

The role of antigen presenting cells in multiple sclerosis

“…In response to IL-17, astrocytes produce CCL2, CCL12, CXCL1, and CXCL2, a distinctly different profile compared to IFN-γ stimulation [13, 60]. Human and murine astrocytes also recruit monocytes and T cells by producing significant amounts of CCL2, CCL5, and CXCL10 in response to TMEV infection and polyI:C stimulation [113, 115, 126]. Astrocytes produce CCL2 during multiple phases of EAE as well [127].…”

“…Unstimulated BALB/c, but not C57Bl/6 astrocytes, were capable of stimulating CD8 + T cells in vitro in a peptide dose-dependent way [129]. Yet TMEV-resistant (C57Bl/6) astrocytes were more efficient in processing and presenting viral antigen than TMEV-susceptible (SJL/J) astrocytes after TMEV infection and IFN-γ stimulation in vitro [126]. Infected or stimulated TMEV-resistant astrocytes had a higher upregulation of MHC class I, vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule 1 (ICAM-1) compared to TMEV-susceptible astrocytes [126].…”

“…Yet TMEV-resistant (C57Bl/6) astrocytes were more efficient in processing and presenting viral antigen than TMEV-susceptible (SJL/J) astrocytes after TMEV infection and IFN-γ stimulation in vitro [126]. Infected or stimulated TMEV-resistant astrocytes had a higher upregulation of MHC class I, vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule 1 (ICAM-1) compared to TMEV-susceptible astrocytes [126]. These differences between C57Bl/6 and SJL/J astrocytes could potentially regulate susceptibility and resistance to the development of demyelinating disease.…”