Macrophage biology in the peripheral nervous system after injury.

Neuroinflammation has positive and negative effects. This review focuses on the roles of macrophage in the PNS. Transection of PNS axons leads to degeneration and clearance of the distal nerve and to changes in the region of the axotomized cell bodies. In both locations, resident and infiltrating macrophages are found. Macrophages enter these areas in response to expression of the chemokine CCL2 acting on the macrophage receptor CCR2. In the distal nerve, macrophages and other phagocytes are involved in clearance of axonal debris, which removes molecules that inhibit nerve regeneration. In the cell body region, macrophage trigger the conditioning lesion response, a process in which neurons increase their regeneration after a prior lesion. In mice in which the genes for CCL2 or CCR2 are deleted, neither macrophage infiltration nor the conditioning lesion response occurs in dorsal root ganglia (DRG). Macrophages exist in different phenotypes depending on their environment. These phenotypes have different effects on axonal clearance and neurite outgrowth. The mechanism by which macrophages affect neuronal cell bodies is still under study. Overexpression of CCL2 in DRG in uninjured animals leads to macrophage accumulation in the ganglia and to an increase in the growth potential of DRG neurons. This increased growth requires activation of neuronal STAT3. In contrast, in acute demyelinating neuropathies, macrophages are involved in stripping myelin from peripheral axons. The molecular mechanisms that trigger macrophage action after trauma and in autoimmune disease are receiving increased attention and should lead to avenues to promote regeneration and protect axonal integrity.