Ligand up-regulation does not correlate with a role for CCR1 in pathogenesis in a mouse model of non-lymphocyte-mediated neurological disease

Abstract

CCR1 ligands, including CCL3, CCL5, and CCL7, are up-regulated in a number of neurological disorders in humans and animal models. CCR1 is expressed by multiple cell types in the central nervous system (CNS), suggesting that receptor signaling by neuronal cell types may influence pathogenesis. In the current study, the authors used a mouse model of retrovirus infection to study the contribution of CCR1 to neuropathogenesis in the absence of lymphocyte recruitment to the CNS. In this model, infection of neonatal mice with the neurovirulent retrovirus Fr98 results in increased expression of proinflammatory chemokines in the CNS, activation of glial cells, and development of severe neurological disease. Surprisingly, no difference in neuropathogenesis was observed between CCR1-sufficient and CCR1-deficient mice following infection with the neuropathogenic virus Fr98. CCR1 was also not necessary for control of virus replication in the brain or virus-induced activation of astroglia. Additionally, CCR1 deficiency did not affect the up-regulation of its ligands, CCL3, CCL5, or CCL7. Thus, CCR1 did not appear to have a notable role in Fr98-induced pathogenesis, despite the correlation between ligand expression and disease development. This suggests that in the absence of inflammation, CCR1 may have a very limited role in neuropathogenesis.

Infection of Cardiomyocytes and Induction of Left Ventricle Dysfunction by Neurovirulent Polytropic Murine Retrovirus

“…Mice were observed daily for clinical signs, which were characterized by hyperexcitability for 2 to 3 days, starting around 14 to 21 days postinfection. This sign was followed by the onset of multiple seizures and then progressive development of ataxia and/or death within a 2-week period (9,24). Some infected mice also showed signs of weight loss compared to littermates and uninfected controls.…”

“…In situ hybridization. In situ hybridization was performed as described previously (9,23). DIG-labeled probes were detected with alkaline-phosphataselabeled anti-DIG antibodies (Roche Molecular Biochemicals) by using the FastRed substrate (Roche Molecular Biochemicals).…”

Innate immunity in the pathogenesis of polytropic retrovirus infection in the central nervous system

“…Analysis of mRNA expression of genes involved in innate immune responses indicated a strong upregulation of proinflammatory cytokine and chemokine gene expression in Fr98-infected mice with clinical signs of disease [9]. The increase in mRNA expression correlated with increased protein expression of these cytokines and chemokines in Fr98-infected mice compared to mock-infected controls [39, 40]. …”

“…Ccl3 , Ccl4 , and Ccl5 mRNA are expressed primarily by uninfected microglia or macrophages, while Ccl2 and Cxcl10 mRNA are expressed by astrocytes, which are also uninfected [39, 42] (unpublished observations). Infiltrating Ccl12 -positive cells are found in brain tissue of pre-clinical mice, but are difficult to detect in mice with clinical disease [42].…”

“…However, mice deficient in either of these receptors develop disease with the same kinetics as wildtype mice [39, 42]. The absence of these receptors did not influence virus replication in the CNS, nor the induction of chemokine expression.…”