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Dorsal Root Ganglion Macrophages Contribute to Both the Initiation and Persistence of Neuropathic Pain

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Dorsal Root Ganglion Macrophages Contribute to Both the Initiation and Persistence of Neuropathic Pain ARTICLE https://doi.org/10.1038/s41467-019-13839-2 OPEN Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain Xiaobing Yu 1*, Hongju Liu1,2, Katherine A. Hamel 3, Maelig G. Morvan 4, Stephen Yu3, Jacqueline Leff1, Zhonghui Guan1, Joao M. Braz 3 & Allan I. Basbaum3* fi 1234567890():,; Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a signi cant 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. 1 Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA. 2 Department of Anesthesiology, Peking Union Medical College Hospital, Beijing, China. 3 Department of Anatomy, University of California San Francisco, San Francisco, California, USA. 4 Department of Medicine, University of California San Francisco, San Francisco, California, USA. *email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:264 | https://doi.org/10.1038/s41467-019-13839-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13839-2 here is now considerable evidence that molecular and macrophages to both the initiation and the maintenance of the Tcellular interactions among spinal dorsal horn neurons and mechanical hypersensitivity. We report that depletion of macro- microglia, the resident macrophages of the central nervous phages in the DRG, but not at the peripheral nerve injury site, can system (CNS), are important contributors to the induction and both prevent the development of and reverse ongoing nerve maintenance of neuropathic pain following peripheral nerve injury-induced mechanical hypersensitivity, in both male and injury1,2. Paralleling the activation of dorsal horn microglia after female mice. In the context of nerve injury, we also uncovered a peripheral nerve injury, several recent studies demonstrated that reciprocal cellular interaction between DRG macrophages and there is also a significant increase in the number of macrophages sensory neurons, one that we suggest is relevant to the DRG in dorsal root ganglia (DRG) ipsilateral to the injury3,4, suggesting macrophage contribution to the neuropathic pain phenotype. that pro-nociceptive neuronal and non-neuronal cellular inter- actions also occur in the DRG. Unclear, however, is the extent to Results which the increase of DRG macrophages contributes to the pain Nerve injury induces macrophage expansion in the DRG. Using phenotype induced by nerve injury. a fluorescence-activated cell sorting (FACS) analysis of dis- To address this question, pharmacological and genetic approa- sociated DRG cells immunostained for the fractalkine receptor, ches have been used to examine the behavioral consequence of CX3CR1, a marker that selectively defines peripheral monocytic depleting DRG macrophages in a nerve injury setting. For example, cells and microglia6,wefirst quantified macrophages in the DRG Cobos et al.5 reported that clodronate-mediated killing of DRG after spared nerve injury (SNI). Figure 1a shows that 4 days after macrophages reduced the mechanical allodynia induced by nerve + – nerve injury (POD4), the CX3CR1 cell population in the L4 and injury. However, other groups could not confirm those findings6 9, L5 DRG, ipsilateral to the nerve injury, increased by 2.9 ± 0.4-fold conceivably due to variability in the efficacy of clodronate5,6.Other compared with the DRG on the contralateral, uninjured side. This studies demonstrated clodronate killing of macrophages in injured ipsilateral expansion of macrophages persisted for at least 4 weeks peripheral nerves and concluded that these macrophages were cri- after the nerve injury (POD28). tical to the neuropathic pain development10,11. However, as these With a view to determining the origin of the injury-induced studies did not examine the DRG, the contribution of DRG mac- macrophage expansion in the DRG, we monitored expression of rophages could not be ruled out. the chemokine receptor CCR2, which reportedly marks infiltrating Selective CSF1 receptor (CSF1R) antagonists have also been + − macrophages23, in a double transgenic CCR2-RFP / /CSF1R- used to induce cell death, by blocking CSF1 signaling to macro- + − GFP / mouse. As expected, we observed significant numbers of phages. However, as these CSF1R antagonists readily cross the + CCR2 macrophages at the peripheral nerve injury site, compared blood–brain barrier (BBB), they concurrently deplete both CNS – with the contralateral uninjured sciatic nerve (Supplementary microglia12 14 and macrophages13. As a result, this approach + Fig. 1A, B); however, we also found many CCR2 macrophages in cannot address selectively the contribution of DRG macrophages. the DRG of uninjured mice (Supplementary Fig. 1C–E), indicating The same limitation confounds the interpretation of results from that CCR2 is not a reliable marker of infiltrating macrophages. In studies that used transgenic mouse lines that express a drug- + a separate experiment, we costained the CX3CR1 macrophages inducible suicide gene, e.g., herpes simplex virus type 1 thymidine with a Ki67 antibody to mark proliferating cells24. One day after kinase (CD11b-TK)15 or diphtheria toxin receptor (CD11b- nerve injury (POD1), FACS analysis showed that the percentage of DTR16, LysM-DTR17, and Cx3cr1-DTR18) in both microglia and + + Ki67 CX3CR1 macrophages in the ipsilateral DRG did not macrophages. As the drugs that induce killing readily cross the differ from the uninjured contralateral DRG (Fig. 1b). However, at BBB, it is impossible to distinguish between the contribution of + + – POD4, the percentage of Ki67 CX3CR1 macrophages in the DRG macrophages and microglia18 20. ipsilateral DRG more than doubled (Fig. 1b and Supplementary A recent report21 took a different approach, using the mac- Fig. 2A, B). Paralleling this result and consistent with previous rophage Fas-induced apoptosis (MAFIA) transgenic mouse immunocytochemical findings25, FACS analysis showed that line22. As for the TK or DTR mice, this line expresses a suicide + + proliferating microglia (Ki67 CX3CR1 ) in the lumbar cord on gene (Fas) under the control of the CSF1R promoter, which is POD4 ipsilateral to the nerve injury increased by more than specifically expressed in macrophages and microglia. In these twofold compared with the contralateral side (Supplementary mice, killing is provoked with an FK-binding protein dimerizer, Fig. 2C). Together, we conclude that axotomy-induced macro- AP20187 (AP). Based on reports that AP does not cross the BBB phage expansion in the DRG involves local proliferation. Although in MAFIA mice22, this approach has been used to kill macro- we cannot rule out infiltration, we favor the view that proliferation phages selectively. Importantly, as this transgenic line coexpresses from resident macrophages predominates. green fluorescent protein (GFP) under control of the same pro- moter, it is possible to monitor the distribution of cells that express the suicide gene and the extent of their depletion. Using DRG macrophages are depleted by systemic AP administra- the MAFIA mice, Shepherd et al.21 demonstrated reduced nerve tion. To determine whether the increase in DRG macrophages injury-induced mechanical hypersensitivity, a hallmark of the contributes to neuropathic pain development, we chose the MAFIA neuropathic pain phenotype, after depletion of circulating transgenic line22, which as noted above, expresses GFP and a drug- monocytes and macrophages at the nerve injury site. Moreover, inducible Fas suicide gene under control of the CSF1R promoter as these authors found that DRG macrophages were spared, they (Supplementary Fig. 3A). The transgene is expressed in CNS concluded that peripheral macrophages, but not those in the microglia (Supplementary Fig. 3B) and tissue macrophages, including DRG, are the critical contributors to nerve injury-induced neu- DRG (Supplementary Fig. 4). To deplete monocytic cells in the ropathic pain21. However, their conclusion was not consistent MAFIA mice, we began our studies with five daily intraperitoneal with an earlier study reporting that selective depletion of per- injections of AP (10 mg kg−1), a macrophage-depleting dose used in ipheral monocytes/macrophages, while sparing DRG macro- earlier studies22.SupplementaryFig.5showsthatthisdosewas phages, had limited impact on neuropathic pain development6. without effect on baseline mechanical threshold (S5A) and weight Given the significant discrepancies in the literature, here we re- (S5B) in wild-type (WT) mice. By contrast,
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