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IL-4 is expressed by eosinophils recruited to nerve and promotes nerve regeneration following injury
Deng Pan, BS1, Lauren Schellhardt, BS1, Daniel A Hunter, RA2, Alison K Snyder-Warwick, MD3, Susan E Mackinnon, MD4 and Matthew D Wood, PhD1, (1)Washington University School of Medicine, St Louis, MO, (2)Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO, (3)Washington University School of Medicine, Saint Louis, MO, (4)Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO

Introduction: Peripheral nerve is capable of regeneration following injury through complex and coordinated efforts by multiple signaling cascade and cell types. IL-4 has recently garnered interest as a cytokine that mediates regeneration across multiple organ systems. However, role and efficacy of IL-4 following nerve injury, and the beneficial effect of exogenous IL-4, is unclear.
Method: IL-4 knockout mice (IL-4KO) and wildtype control (WT) are used for animal model. Nerve injury is created via crush with needle driver. Immunofluorescence and flow cytometry were used for characterization of cells in nerve and axonal regeneration. Grid walk was used to measure functional recovery.
Results: Following peripheral nerve injury, IL-4 expressing cells are found preferentially in the nerve compared to dorsal root ganglia or denervated muscles. Eosinophils are the majority of IL-4 expressing cells. Loss of IL-4 in IL-4KO impeded the regeneration of axons and delayed functional recovery compared to WT. Loss of IL-4 also delayed innervation of neuromuscular junctions. Both macrophages and neurons express IL-4 receptor and thus are potential targets of IL-4. In vitro culture of neurons with IL-4 promoted neuron axonal extension, and myelination. Loss of IL-4 also affected macrophage accumulation, shifted their phenotype towards a CD206- phenotype, and altered gene expression. Finally, systemically delivered exogenous IL-4 shifts macrophage phenotype within injured nerve, and promote early regeneration of axons but did not affect functional recovery.
Conclusion: IL-4 expressed by eosinophils within the injured nerve promotes nerve regeneration and functional recovery through its effects of neurons and macrophages. Systemic exogenous IL-4 promoted axonal regeneration.



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