Schwann cell dedifferentiation and proliferation is a prerequisite to axonal regeneration in the injured peripheral nervous system. The neuregulin (NRG) family of growth and differentiation factors may play a particularly important role in this process, because these axon-associated molecules are potent Schwann cell mitogens and differentiation factors in vitro. We have examined Schwann cell DNA synthesis and the expression of NRGs and their receptors, the erbB membrane tyrosine kinases, in rat sciatic nerve, sensory ganglia, and spinal cord 0 -30 d postaxotomy. Analysis of NRG cDNAs from these tissues revealed several novel splice variants and showed that cells endogenous to injured nerve express NRG mRNAs. A selective induction of mRNAs encoding the glial growth factor (GGF) subfamily of NRGs occurs in nerve beginning 3 d postaxotomy and thus coincides with the onset of Schwann cell DNA synthesis. In later stages of Wallerian degeneration, however, Schwann cell mitogenesis markedly decreases, whereas elevated GGF expression persists. Of the four known erbB kinases, Schwann cells express both erbB2 and erbB3 receptors over the entire interval studied. Expression of erbB2 and erbB3 is coordinately induced in response to axotomy, indicating that Schwann cell responses to NRGs may be modulated by changes in receptor density. Neuregulin (including transmembrane precursors) and erbB protein are associated with Schwann cells postaxotomy. Thus, in contrast to the concept of NRGs as axon-associated mitogens, our findings suggest that NRGs produced by Schwann cells themselves may be partially responsible for Schwann cell proliferation during Wallerian degeneration, probably acting via autocrine or paracrine mechanisms.

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Skin wound repair requires a coordinated program of epithelial cell proliferation and differentiation as well as resistance to invading microbes. However, the factors that trigger epithelial cell proliferation in this inflammatory process are incompletely understood. Recent studies from our lab and others demonstrate that IL-27 is produced by activated antigenpresenting cells in the skin upon skin damage and is shown to exert both pro-inflammatory and anti-inflammatory effects. The potential functional role of IL-27 in wound repair is currently unknown. Here, we demonstrate that IL-27 is rapidly and transiently produced by CD301b + monocyte-derived macrophages and DC in the skin following injury. The functional role of IL-27 and CD301b + cells is demonstrated by the finding that CD301b-depleted mice exhibit delayed wound closure in vivo which could be rescued by topical IL-27 treatment. Furthermore, genetic ablation of IL-27 receptor (Il27Ra-/-) attenuates wound healing, suggesting an essential role for IL-27 signaling in skin regeneration in vivo. Mechanistically, IL-27 feeds back on keratinocytes to stimulate cell proliferation and re-epithelialization in the skin, whereas IL-27 leads to suppression of keratinocyte terminal differentiation. Finally, we identify that IL-27 potently increases expression of the anti-viral oligoadenylate synthase 2 (OAS2), however does not affect expression of anti-bacterial human beta defensin 2 (HBD2) or regenerating islet-derived protein 3-alpha (REGIIIa). Together, our data suggest a previously unrecognized role for IL-27 in regulating epithelial cell proliferation and anti-viral host defense during the normal wound healing response. Our results may have major implications in our understanding of how keratinocyte proliferation and protective antiviral immunity is regulated during wound repair.

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