Macrophage-Derived Amphiregulin Enhances Schwann Cell Phagocytosis Through the EGFR/CTSS Signaling Pathway

Although Schwann cells are non-professional phagocytes, their phagocytic function significantly contributes to myelin debris clearance, a critical process for Wallerian degeneration. However, whether their phagocytic capacity is modulated by professional phagocytes like macrophages remains unknown. This study demonstrates that following nerve injury, macrophages can secrete amphiregulin (AREG) to enhance the phagocytic capability of Schwann cells. Using an Areg conditional knockout (cKO) mouse model, we identified that macrophage-derived AREG activates the epidermal growth factor receptor (EGFR) on Schwann cells and upregulates Cathepsin S (CTSS) expression. CTSS restoration rescued the phagocytic defect in Schwann cells treated with conditioned medium from cKO. These findings reveal a novel paracrine mechanism wherein macrophages regulate Schwann cell phagocytosis via the AREG-EGFR-CTSS axis, highlighting a potential target for promoting myelin debris clearance and accelerating Wallerian degeneration after nerve injury.