Nerve injury and inflammatory cytokines regulate Schwann cell phenotype and function

Abstract

Schwann cells subserve important functions in both normal and regenerating peripheral nerve. After nerve injury, coordinated phenotypic changes occur in Schwann cells that assist in regenerative processes. Local cytokine release is thought to stimulate the responses of Schwann cells within the original basal lamina tube surrounding the degenerating axon. We have used both n vitro and in vivo approaches to examine the effects of inflammatory cytokines and nerve injury on Schwann cell phenotype and function. Cultured Schwann cells assume a dedifferentiated phenotype, divide very slowly, and are weakly coupled to one another by gap junction channel(s). Although the molecular nature of this connexin remains to be defined, it is distinct from connexin32 which is expressed by myelinating Schwann cells in normal nerve. Treatment of cultured Schwann cells with TGF{dollar}\beta{dollar} induces cellular differentiation and significantly decreases gap junctional coupling. Moreover, TNF{dollar}\alpha{dollar} inhibits both Schwann cell proliferation and junctional coupling. By contrast, forskolin combined with bovine pituitary extract stimulates Schwann cell proliferation and significantly enhances junctional coupling. NDF{dollar}\beta{dollar} initially decreases junctional coupling, but induces expression of a new channel and enhances junctional coupling coincident with a significant increase in Schwann cell proliferation. These data suggest that factors that stimulate proliferation enhance coupling among Schwann cells whereas factors that inhibit proliferation or induce differentiation of basal state cells decrease coupling. In the sciatic nerve, there is a rapid decrease in connexin32 after crush injury, and re-expression as regeneration and remyelination proceeds. Connexin43, by contrast, is transiently elevated in endoneurial fibroblasts. Myelinating Schwann cells are normally not coupled; however, after crush injury coupling among distal Schwann cells is enhanced. A specific hypothesis that has emerged from these studies is that cytokines regulation of gap junctional communication among Schwann cells may play a critical role in Schwann cell injury responses and successful nerve regeneration, and indicate the involvement of gap junction proteins in addition to connexin32. In toto, these studies indicate that inflammatory cytokines released after nerve injury regulate Schwann cell phenotype, proliferation, and function.