Myeloid cells protect corneal nerves against sterile injury through negative-feedback regulation of TLR2–IL-6 axis

BACKGROUND: Mounting evidence suggests that the immune system plays detrimental or protective roles in nerve injury and repair. MAIN BODY: Herein we report that both CD11b(hi)Ly6G(hi) and CD11b(hi)Ly6C(hi)Ly6G(lo) myeloid cells are required to protect corneal nerves against sterile corneal injury. Selective depletion of CD11b(hi)Ly6G(hi) or CD11b(hi)Ly6C(hi)Ly6G(lo) cells resulted in aggravation of corneal nerve loss, which correlated with IL-6 upregulation. IL-6 neutralization preserved corneal nerves while reducing myeloid cell recruitment. IL-6 replenishment exacerbated corneal nerve damage while recruiting more myeloid cells. In mice lacking Toll-like receptor 2 (TLR2), the levels of IL-6 and myeloid cells were decreased and corneal nerve loss attenuated, as compared to wild-type and TLR4 knockout mice. Corneal stromal fibroblasts expressed TLR2 and produced IL-6 in response to TLR2 stimulation. CONCLUSION: Collectively, our data suggest that CD11b(hi)Ly6G(hi) and CD11b(hi)Ly6C(hi)Ly6G(lo) myeloid cells confer corneal nerve protection under sterile injury by creating a negative-feedback loop to suppress the upstream TLR2–IL-6 axis that drives corneal nerve loss.