During nerve fiber degeneration in the peripheral nervous system monocytes are promptly, abundantly, and selectively recruited from the circulation, myelin debris is rapidly cleared, and, presumably in part as a result of macrophage contributions, regeneration (in the rodent) is rapid and extensive. In contrast, during fiber degeneration in the central nervous system (CNS) hematogenous monocytes fail to be recruited, and CNS myelin debris, known to be inimical to axonal outgrowth, is cleared very slowly. Several lines of evidence have raised the possibility that the presence of macrophages within degenerating CNS pathways might increase the likelihood of successful axonal elongation. Recent data from the Griffin and Ransohoff labs suggest that a product of denervated Schwann cells, the C-C chemokine, monocyte chemoattractant protein-1 (MCP-1), provides one important mechanism. The overall goals of this project are: To understand fully the mechanism(s) by which monocytes are recruited into the degenerating PNS and to develop preparations that fail to recruit macrophages during Wallerian degeneration, focusing initially on the hypothesis that activation of the MCP-1 receptor CCR2 is necessary and sufficient to recruit hematogenous monocytes; and to test the hypothesis that providing the degenerating CNS with the capability to recruit circulating monocytes will result in prompt clearance of myelin debris and increased axonal regeneration. The planned studies will characterize the chemokine profiles produced by Schwann cells during Wallerian degeneration, and determine whether MCP-1 and CCR2 knockouts are unable to recruit macrophages normally. We will test a widely cited hypothesis, that complement activation occurs on PNS myelin during Wallerian degeneration, so that complement activation products are chemotropic to macrophages. The final series of experiments will characterize chemokine production and macrophage recruitment in the dorsal columns and the optic nerves of normal mice during Wallerian degeneration, and compare the results to those in transgenic mice in which MCP-1 expression is governed by the GFAP promotor. We anticipate that abundant macrophage recruitment will be seen during CNS fiber degeneration in these animals, and that CNS myelin debris will be rapidly cleared. Such animals will provide the ideal system in which to test the possibility that CNS regeneration will be substantially improved by permitting macrophage recruitment.
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