Monocyte recruitment and myelin removal are delayed following spinal cord injury in mice with CCR2 chemokine receptor deletion

Abstract

The inflammatory response initiated after spinal cord injury (SCI) is characterized by the accumulation of macrophages at the impact site. Monocyte chemoattractant protein-1 (MCP-1) is a strong candidate for mediating chemotaxis of monocytes to the injured nervous system. To help in defining the role of MCP-1 in inflammation after SCI, we evaluated the time course of macrophage accumulation for 2 weeks following a midthoracic spinal cord contusion injury in mice lacking CCR2, a principal receptor for MCP-1. Mice with a deletion of CCR2 resulted in significantly reduced Mac-1 immunoreactivity restricted to the lesion epicenter at 7 days postinjury. The regions devoid of Mac-1 immunoreactivity corresponded to areas of reduced myelin degradation at this time. By 14 days postinjury, however, there were no differences in Mac-1 staining between CCR2 (+/+) and CCR2 (-/-) mice. Analyses of mRNA levels by RNase protection assay (RPA) revealed increases in MCP-1 as well as MCP-3 and MIP-2 mRNA at 1 day postinjury compared with 7 day postinjury. There were no differences in chemokine expression between CCR2-deficient mice and wild-type littermate controls. The CCR2-deficient mice also exhibited reduced expression of mRNA for chemokine receptors CCR1 and CCR5. Together, these results indicate that chemokines acting through CCR2 contribute to the early recruitment of monocytes to the lesion epicenter following SCI.

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

“…30 -32 Decreased MIP-2 expression would be expected to cause diminished recruitment of CCR2-expressing myelomonocytic lineage cells (blood monocytes and tissue macrophages) from the circulation. [33][34][35][36] Therefore, our detection of reduced CCR2 mRNA expression in the spinal cord was likely because of the diminished recruitment of CCR2-expressing monocytes/macrophages because of decreased MIP-2. Although beyond the scope of the present study, future experiments evaluating the phenotype and expressed genes of blood cells before CNS infiltration should contribute additional useful information necessary for understanding the development of the inflammatory response during disease and E2 protection.…”

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

“…Though CCL2 is the principal endogenous CCR2 agonist, alternative chemokines can also activate CCR2 and may contribute to our findings. For example, CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), and CCL12 (MCP-5) can activate CCR2 in mice (Ma et al, 2002;Mantovani et al, 2004). We previously found that, in addition to CCL2, the release of CCL5 and CCL12 are markedly increased in opiate and/or Tat-exposed astrocytes , and concluded that CCL5, CCL12 or perhaps another chemokine contributed directly to opiate and HIV-1-induced reactive glial changes .…”

Metalloproteinases Control Brain Inflammation Induced by Pertussis Toxin in Mice Overexpressing the Chemokine CCL2 in the Central Nervous System

“…CCL2, previously named MCP-1, is critical for cellular entry to the CNS in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS (6). Blockade of CCL2 function in systems of nonimmune-mediated CNS infiltration curbs migration of leukocytes to sites of damage (7)(8)(9). Tg expression of CCL2 targeted to oligodendrocytes leads to perivascular accumulation of leukocytes in the brain without clinical symptoms (10).…”