Lesion-associated Expression of Transforming Growth Factor-Beta-2 in the Rat Nervous System: Evidence for Down-regulating the phagocytic Activity of Microglia and Macrophages

The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)β2 in vitro and studied TGFβ-2mRNA and protein expression two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF-β2 immunoreactivity. In contrast, TGF-β2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase In line with its differential lesion-associated expression pattern, exogenous TGF-β2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF-β2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury.