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GATA1 knockout mice have decreased eosinophils, macrophages, and nerve regeneration after segmental nerve injury
Adam Liebendorfer, MA, MSCI1; Michael J Finnan, MS2; Lauren Schellhardt, BS3; Jonathon Schofield, BS1; Jesús A Acevedo-Cintron, BS2; Dan A. Hunter, RA4; Snyder-Warwick K Alison, MD5; Susan Mackinnon, MD6; Matthew Wood, PhD7
1Washington University in St. Louis, St. Louis, MO; 2Washington University School of Medicine, St. Louis, MO; 3Washington University School of Medicine, St Louis, MO; 4Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St Louis, MO; 5Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO; 6Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO; 7Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO

INTRODUCTION: The adaptive immune system has garnered attention for its role in regulating cytokines involved in nerve regeneration, particularly T-cells through IL-4. Previous work demonstrated that eosinophils represent the majority of IL-4-expressing cells in injured nerves. Here, we assessed the role of eosinophils in nerve regeneration through IL-4 signaling.
METHODS: GATA1 KO mice containing minimal eosinophils and wild-type (WT) mice were randomized to groups to assess regenerative responses after a sciatic nerve injury and/or repair of a nerve gap using a conduit. Following injury and/or repair, immunohistochemistry and gene analysis were used to characterize the microenvironment within the regenerating nerve gap. Function was evaluated by behavioral analysis using a grid grip test. The number of neurons regenerating axons was determined through retrograde tracing.
RESULTS: Retrograde tracing of uninjured nerve revealed no baseline difference among uninjured mice (WT vs GATA1 KO) motoneuron or sensory neuron quantities. After a repaired nerve injury, retrograde tracing of axons regenerating distal to the repair site revealed there was no difference in motoneurons regenerating axons 2 weeks after repair amongst groups. But, GATA1 KO mice exhibited decreased sensory neurons regenerating axons compared to WT. Immunohistochemical analysis after repair of a nerve gap showed GATA1 KO had a decreased proportion of eosinophils (Siglec F) within the gap. Additionally, GATA1 KO mice had fewer of M2 macrophages (CD 68+, CD 206+) and macrophages overall (CD 68+) in the gap compared to WT mice. Following repair of a nerve gap, there were no differences in functional recovery, as based on grid grip analysis, nor differences in quantities of neurons (both sensory or motor) regenerating their axons by 16 weeks amongst groups.
CONCLUSIONS: Eosinophils affect early sensory axon regeneration as evidenced by decreased sensory neurons regenerating axons after injury, which could be due to eosinophils’ effect on type 2 cytokine expression and in turn macrophage phenotype. However, functional recovery and final nerve regeneration are not affected by an absence of eosinophils suggesting a compensatory mechanism to overcome initially affected early nerve regeneration


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