Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment andactivation of Ly6Clo/iNOS+ macrophages

Abstract

Macrophages exert divergent effects in the injured CNS, causing either neurotoxicity or regeneration. The mechanisms regulating thesedivergent functions are not understood but can be attributed to the recruitment of distinct macrophage subsets and the activation ofspecific intracellular signaling pathways. Here, we show that impaired signaling via the chemokine receptor CX3CR1 promotes recoveryafter traumatic spinal cord injury (SCI) in mice. Deficient CX3CR1 signaling in intraspinal microglia and monocyte-derived macrophages(MDMs) attenuates their ability to synthesize and release inflammatory cytokines and oxidative metabolites. Also, impaired CX3CR1signaling abrogates the recruitment or maturation of MDMs with presumed neurotoxic effects after SCI. Indeed, in wild-type mice,Ly6Clo/Inos+/MHCII+/CD11c -MDMsdominate the lesion site, whereasCCR2+/Ly6Chi/MHCII-/CD11c+/monocy tes predominate inthe injured spinal cord of CX3CR1-deficient mice. Replacement of wild-type MDMs with those unable to signal via CX3CR1 resulted inanatomical and functional improvements after SCI. Thus, blockade ofCX3CR1signaling represents a selective anti-inflammatory therapythat is able to promote neuroprotection, in part by reducing inflammatory signaling in microglia and MDMs and recruitment of a novelmonocyte subset. © 2011 the authors.