Macrophages and their initiation of acute inflammation have been defined to be functionally important in tissue repair and regeneration. In injury-induced production of macrophage migration inhibitory factor (MIF), which has been described as a pleiotropic protein that participates in multiple cellular and biologic processes, it is unknown whether it is involved in the regulation of macrophage events during the epimorphic regeneration. In the model of gecko tail amputation, the protein levels of gecko MIF (gMIF) have been determined to be significantly increased in the nerve cells of the spinal cord in association with the recruitment of macrophages to the lesion site. gMIF has been shown to interact with the CD74 receptor to promote the migration of macrophages through activation of Ras homolog gene family member A and to trigger inflammatory responses through MAPK signaling pathways. The determination of microsphere phagocytosis also indicated that gMIF could enhance macrophage phagocytosis. gMIF-mediated recruitment and activation of macrophages have been found to be necessary for gecko tail regeneration, as evidenced by the depletion of macrophages using clodronate liposomes. The results present a novel function of MIF during the epimorphic regeneration, which is beneficial for insights into its pleiotropic property.

No abstract

Adult mammalian astrocytes are sensitive to inflammatory stimuli in the context of neuropathology or mechanical injury, thereby affecting functional outcomes of the central nervous system (CNS). In contrast, glial cells residing in the spinal cord of regenerative vertebrates exhibit a weak astroglial reaction similar to those of mammals in embryonic stages. Macrophage migration inhibitory factor (MIF) participates in multiple neurological disorders by activation of glial and immune cells. However, the mechanism of astrocytes from regenerative species, such as gecko astrocytes (gAS), in resistance to MIF-mediated inflammation in the severed cords remains unclear. Here, we compared neural stem cell markers among gAS, as well as adult (rAS) and embryonic (eAS) rat astrocytes. We observed that gAS retained an immature phenotype resembling rat eAS. Proinflammatory activation of gAS with gecko (gMIF) or rat (rMIF) recombinant protein was unable to induce the production of inflammatory cytokines, despite its interaction with membrane CD74 receptor. Using cross-species screening of inflammation-related mediators from models of gMIF- and rMIF-induced gAS and rAS, we identified Vav1 as a key regulator in suppressing the inflammatory activation of gAS. The gAS with Vav1 deficiency displayed significantly restored sensitivity to inflammatory stimuli. Meanwhile, gMIF acts to promote the migration of gAS through regulation of CXCL8 following cord lesion. Taken together, our results suggest that Vav1 contributes to the regulation of astrocyte-mediated inflammation, which might be beneficial for the therapeutic development of neurological diseases.

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Schwann cells are not only myelinating cells, but also function as immune cells and express numerous innate pattern recognition receptors, including the Toll-like receptors. Injury to peripheral nerves activates an inflammatory response in Schwann cells. However, it is unclear whether specific endogenous damage-associated molecular pattern molecules are involved in the inflammatory response following nerve injury. In the present study, we demonstrate that a key damage-associated molecular pattern molecule, high mobility group box 1 (HMGB1), is upregulated following rat sciatic nerve axotomy, and we show colocalization of the protein with Schw-ann cells. HMGB1 alone could not enhance expression of Toll-like receptors or the receptor for advanced glycation end products (RAGE), but was able to facilitate migration of Schwann cells. When Schwann cells were treated with HMGB1 together with lipopolysaccharide, the expression levels of Toll-like receptors and RAGE, as well as inflammatory cytokines were upregulated. Our novel findings demonstrate that the HMGB1 pathway activates the inflammatory response in Schwann cells following peripheral nerve injury.