Conditional Ablation of Astroglial CCL2 Suppresses CNS Accumulation of M1 Macrophages and Preserves Axons in Mice with MOG Peptide EAE

Abstract

Current multiple sclerosis (MS) therapies only partially prevent chronically worsening neurological deficits, which are largely attributable to progressive loss of CNS axons. Prior studies of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), a model of MS, documented continued axon loss for months after acute CNS inflammatory infiltrates had subsided, and massive astroglial induction of CCL2 (MCP-1), a chemokine for CCR2 ϩ monocytes. We now report that conditional deletion of astroglial CCL2 significantly decreases CNS accumulation of classically activated (M1) monocyte-derived macrophages and microglial expression of M1 markers during the initial CNS inflammatory phase of MOG peptide EAE, reduces the acute and long-term severity of clinical deficits and slows the progression of spinal cord axon loss. In addition, lack of astroglial-derived CCL2 results in increased accumulation of Th17 cells within the CNS in these mice, but also in greater confinement of CD4 ϩ lymphocytes to CNS perivascular spaces. These findings suggest that therapies designed to inhibit astroglial CCL2-driven trafficking of monocyte-derived macrophages to the CNS during acute MS exacerbations have the potential to significantly reduce CNS axon loss and slow progression of neurological deficits.

Role of the receptor Mas in macrophage-mediated inflammation in vivo

“…Therefore, the receptor Mas may be an interesting therapeutic target to treat autoimmune diseases via regulating inflammatory processes. A specific activation of Mas, e.g., via agonists like AVE 0991, may impair macrophage migration through the BBB or in the vessel wall, thus limiting inflammation in the CNS or the vascular system (28,34,35). (B and C) In ApoEKO mice, Mas deficiency leads to increased oxidative stress measured by urinary 8-isoprostane and aortic nitrotyrosine expression levels (measurements were repeated for a total of three times; n = 6-8, *P < 0.05, mean ± SEM).…”

Inflammation in the CNS: Advancing the Field Using Intravital Imaging

“…Those T cells that are present in the circulating cerebral spinal fluid under homeostatic conditions are enriched for memory T cell markers and CXCR3 expression (111); however, a role for specific receptors in T cell immune surveillance of the CNS has not been defined. The atypical structure of the CNS parenchyma under homeostatic conditions may require distinct mechanisms of T cell interstitial motility from those utilized by T cells recruited to the CNS by inflammation and infection (112).…”

“…Third, the combination of the presence of kynurenine metabolites and TRP depletion increases the number of regulatory T cells positive for forkhead box P3 (FOXP3 + ) via TGFβ induction and its impact on naive T cells (110). Moreover, downstream TRP catabolites are able to shift dendritic cells to a tolerogenic phenotype independent of the microenvironment TRP levels, i.e., without functional IDO-1 (111,112). Therefore, IDO-1 competent dendritic cells also contribute to KP-mediated immune-suppression by contributing to a tolerogenic environment.…”

“…Astrocyte-conditioned media are only partly effective in maintaining the ramified morphology of microglia, because astrocytes provide not only soluble (e.g., granulocyte macrophage colonystimulating factor and colony-stimulating factor 1) but also nondiffusible factors. An astrocyte feeder layer is commonly used to support microglia and neuronal cultures alike (112,113). This can be achieved using a two-chamber culture system comprising an enriched microglia culture separated from an enriched astrocyte culture by an inset with a porous membrane.…”

Interfering with the CCL2–glycosaminoglycan axis as a potential approach to modulate neuroinflammation

“…Perivascular and parenchymal foamy macrophages do not express CCL2 protein and are likely to contribute to resolution of inflammation by inhibiting further lesion development and promoting lesion repair [13,14]. On this line of evidence it has recently been reported that in a murine model of experimental autoimmune encephalomyelitis, mice with conditional astroglial ablation of CCL2 showed a reduced severity of pathology due to less spinal cord axonal loss [15] (Moreno et al 2014).…”