Abstract
Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.
Highlights
Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG)
Using a fluorescence-activated cell sorting (FACS) analysis of dissociated DRG cells immunostained for the fractalkine receptor, CX3CR1, a marker that selectively defines peripheral monocytic cells and microglia[6], we first quantified macrophages in the DRG after spared nerve injury (SNI)
One day after nerve injury (POD1), FACS analysis showed that the percentage of Ki67+CX3CR1+ macrophages in the ipsilateral DRG did not differ from the uninjured contralateral DRG (Fig. 1b)
Summary
Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Based on reports that AP does not cross the BBB in MAFIA mice[22], this approach has been used to kill macrophages selectively As this transgenic line coexpresses green fluorescent protein (GFP) under control of the same promoter, it is possible to monitor the distribution of cells that express the suicide gene and the extent of their depletion. Using the MAFIA mice, Shepherd et al.[21] demonstrated reduced nerve injury-induced mechanical hypersensitivity, a hallmark of the neuropathic pain phenotype, after depletion of circulating monocytes and macrophages at the nerve injury site. As these authors found that DRG macrophages were spared, they concluded that peripheral macrophages, but not those in the DRG, are the critical contributors to nerve injury-induced neuropathic pain[21]. In the context of nerve injury, we uncovered a reciprocal cellular interaction between DRG macrophages and sensory neurons, one that we suggest is relevant to the DRG macrophage contribution to the neuropathic pain phenotype
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
