MCP-1 and CCR2 Contribute to Non-Lymphocyte-Mediated Brain Disease Induced by Fr98 Polytropic Retrovirus Infection in Mice: Role for Astrocytes in Retroviral Neuropathogenesis

Abstract

Virus infection of the central nervous system (CNS) often results in chemokine upregulation. Although often associated with lymphocyte recruitment, increased chemokine expression is also associated with non-lymphocyte-mediated CNS disease. In these instances, the effect of chemokine upregulation on neurological disease is unclear. In vitro, several chemokines including monocyte chemotactic protein 1 (MCP-1) protect neurons from apoptosis. Therefore, in vivo, chemokine upregulation may be a protective host response to CNS damage. Alternatively, chemokines may contribute to pathogenesis by stimulating intrinsic brain cells or recruiting macrophages to the brain. To investigate these possibilities, we studied a neurovirulent retrovirus, Fr98, that induces severe non-lymphocyte-mediated neurological disease and causes the upregulation of several chemokines that bind to chemokine receptors CCR2 and CCR5. Knockout mice deficient in CCR2 had reduced susceptibility to Fr98 pathogenesis, with significantly fewer mice developing clinical disease than did wild-type controls. In contrast, no reduction in Fr98-induced disease was observed in CCR5 knockout mice. Thus, signaling through CCR2, but not CCR5, plays an important role in Fr98-mediated pathogenesis. Three ligands for CCR2 (MCP-1, MCP-3, and MCP-5) were upregulated during Fr98 infection of the brain. Antibodyblocking experiments demonstrated that MCP-1 was important for retrovirus-induced neurological disease. In situ hybridization analysis revealed that MCP-1 was expressed by glial fibrillary acidic protein-positive astrocytes. Thus, astrocytes, previously not thought to play an effector role in the disease process were found to contribute to pathogenesis through the production of MCP-1. This study also demonstrates that chemokines can mediate pathogenesis in the CNS in the absence of lymphocytic infiltrate and gives credence to the hypothesis that chemokine upregulation is a mechanism by which retroviruses such as human immunodeficiency virus induce neurological damage.

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…Likewise, CNS disease associated with inflammatory responses in the CNS has been described in newborn mice infected with non-lytic viruses such as murine leukemia virus or Borna disease virus. [70][71][72][73] Furthermore, corticosteroid treatment, which modulates inflammatory responses, corrected the MCMVinduced morphological deficits within the cerebellum of infected mice. 56 Prednisolone treatment also corrected abnormalities in the transcription of developmentally regulated genes (decreased GABRA6 and CDK5 and increased gli1 and N-myc expression) and decreased the expression of inflammatory cytokines (TNFa, IFN-b and IFN-c).…”

Analysis of the Neuroinflammatory Response to TLR7 Stimulation in the Brain: Comparison of Multiple TLR7 and/or TLR8 Agonists

“…Mice, at ϳ48 h after birth, were anesthetized by hypothermia, and 10 l (5 l/hemisphere) of the appropriate TLR agonist or vehicle control was inoculated into the lateral ventricles using a 33-gauge needle and a Hamilton syringe according to a previously established protocol (45,46). Correct ventricular inoculation was confirmed by observing trypan blue staining in the ventricles (45,46).…”

“…Correct ventricular inoculation was confirmed by observing trypan blue staining in the ventricles (45,46). Mice were inoculated icv with either 2 g of LPS, 50 g (200 nmol) of imiquimod, or 10 l of vehicle control (0.2% trypan blue in PBS).…”

“…We analyzed cells for Ccl2 mRNA expression since this chemokine is often associated with viral infection in the CNS (45,52). Ccl2-positive cells in imiquimodtreated mice were located at the edges of the ventricles and spread out into the tissue (Fig.…”

Role of Erk1/2 activation in prion disease pathogenesis: Absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression

“…Thus, it is difficult to determine whether these molecules have a causative role in disease where upregulation has been detected. Our laboratory has previously used knockout (KO) mice deficient in cytokines or chemokine receptors to show an active role for these molecules in a retrovirus-induced CNS disease in vivo (Peterson et al, 2004b;Peterson et al, 2004a). In the present study, we used a similar strategy to compare scrapie infection in KO mice lacking CCR1 expression (CCR1 KO mice) versus wild-type (WT) control mice.…”