CD200R1 Agonist Attenuates Mechanisms of Chronic Disease in a Murine Model of Multiple Sclerosis

Abstract

To assess the effects and mechanisms of a CD200R1 agonist administered during the progressive stage of a multiple sclerosis model, we administered CD200R1 agonist (CD200Fc) or control IgG2a during the chronic phase of disease (days 10 -30) in mice with experimental autoimmune encephalomyelitis (EAE), induced using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) peptide. We found that administration of CD200Fc during the chronic stages of EAE reduced disease severity, demyelination, and axonal damage, through the modulation of several key disease mechanisms. CD200Fc treatment suppressed macrophage and microglial accumulation within the CNS, in part through downregulation of adhesion molecules VLA-4 and LFA-1, which are necessary for macrophage migration. Additionally, expression of activation markers MHC-II and CD80 and production of proinflammatory cytokines IL-6, tumor necrosis factor-␣, and nitric oxide by CD11bϩ cells were decreased in both the spleen and CNS in CD200Fc-treated animals. Antigen-presenting cell function in the spleen and CNS was suppressed in CD200Fc-treated mice, but there were no significant alterations on T cell activation or phenotype. CD200Fc increased apoptosis of CD11b ϩ cells but not astrocytes. In contrast, addition of CD200Fc treatment protected oligodendrocytes from apoptosis in vitro and in vivo. Our results demonstrate that CD200R1 agonists modulate both myeloid-and non-myeloid-related mechanisms of chronic disease in the EAE model and may be effective in the treatment of progressive multiple sclerosis and other neurodegenerative diseases.

CNS inflammation and neurodegeneration

“…Administration of a CD200R-blocking antibody to Lewis rats exacerbated EAE (63), and CD200-deficient mice experienced earlier onset of EAE, with increased microglia/macrophage accumulation and activation in the CNS as demonstrated by increased expression of inducible NOS (iNOS) (65). We found that administration of a CD200R1 agonist attenuated disease in a chronic MS model (66). Enhanced CD200 expression was associated with reduced Wallerian degeneration in the slow Wallerian degeneration (Wld s ) mouse (67), a spontaneously occurring mutant with the unique phenotype of protection against several forms of axonal injury (68)(69)(70)(71).…”

Dysregulated neuronal–microglial cross-talk during aging, stress and inflammation

“…While lack of CD200 signaling exacerbates neuroinflammation, enhanced CD200-CD200R signaling either via increased neuronal expression of CD200 or administration of the CD200R agonist CD200-Fc fusion protein, can down-regulate microglia activation, reduce pro-inflammatory cytokine expression and maintain neuronal integrity in the rodent experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) (Chitnis, et al, 2007, Liu, et al, 2010). Recent findings in human patients also support the role of CD200 in regulating microglia activation in neuropathological conditions.…”

An optimized method to process mouse CNS to simultaneously analyze neural cells and leukocytes by flow cytometry

“…Traditionally, a Percoll TM gradient has been used to remove cell debris and myelin from these dissociated adult CNS tissue preparations (Allen et al, 1993;Ford et al, 1995;Sedgwick et al, 1991). However, others have used a single 37% (v/v) Percoll TM step to isolate microglia and infiltrating leukocytes (Kivisakk et al, 2009;La Flamme et al, 2003;Liu et al, 2010;Salem et al, 2011). Percoll TM is a suspension of colloidal silica particles coated with polyvinylpyrrolidone (Pertoft et al, 1978).…”