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Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury.

ABSTRACT: Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1⁺ spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1⁺ spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.

SUBMITTER: Niehaus JK

PROVIDER: S-EPMC8068642 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury.

Niehaus Jesse K JK Taylor-Blake Bonnie B Loo Lipin L Simon Jeremy M JM Zylka Mark J MJ

Neuron 20210304 8

Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1<sup>+</sup> spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured ...[more]

PMID: 33667343

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Project description:BackgroundDeficient endogenous pain modulation and increased nociceptive excitability are key features of central sensitization and can be assessed in humans by conditioned pain modulation (CPM, anti-nociceptive) and temporal summation of pain (TSP, pro-nociceptive), respectively. This study aimed to investigate these measures as proxies for central sensitization in subjects with chronic neuropathic pain (NP) after spinal cord injury (SCI).MethodsIn paraplegic subjects with NP (SCI-NP; n = 17) and healthy controls (HC; n = 17), parallel and sequential sham-controlled CPM paradigms were performed using pressure pain threshold at the hand, that is, above lesion level, as test stimulus. The conditioning stimulus was a noxious cold (verum) or lukewarm water bath (sham) applied contralaterally. Regarding pro-nociceptive mechanisms, a TSP protocol with individually-adjusted pressure pain stimuli at the thenar eminence was used. CPM and TSP magnitudes were related to intensity and spatial extent of spontaneous NP.ResultsNeither the parallel nor sequential sham-controlled CPM paradigm showed any significant inhibition of above-level pressure pain thresholds for SCI-NP or HC. Accordingly, no group difference in CPM capacity was found, however, subjects with more intense spontaneous NP showed lower inhibitory CPM capacity. TSP was observed for both groups but was not enhanced in SCI-NP.ConclusionsOur results do not support altered above-level anti- or pro-nociceptive mechanisms in SCI-NP compared with HC; however, they also highlight the relevance of spontaneous NP intensity with regards to the capacity of endogenous pain modulation in SCI subjects.SignificanceCentral sensitization encompasses deficient endogenous pain modulation and increased nociceptive excitability. These two mechanisms can be assessed in humans by conditioned pain modulation and temporal summation of pain, respectively. Our data demonstrates a lack of descending pain inhibition only in subjects with severe neuropathic pain which may hint towards central sensitization at spinal and/or supra-spinal levels. Disentangling the mechanisms of endogenous pain modulation and neuronal hyperexcitability might improve mechanism-based treatment of neuropathic pain in subjects with spinal cord injury.

Project description:BackgroundNeuro-immune interaction underlies chronic neuroinflammation and aberrant sensory processing resulting in neuropathic pain. Despite the pathological significance of both neuroinflammation-driven peripheral sensitization and spinal sensitization, the functional relationship between these two distinct events has not been understood.MethodsIn this study, we determined whether inhibition of inflammatory macrophages by administration of α4β2 nicotinic acetylcholine receptor (nAChR) agonists improves neuropathic pain and affects microglial activation in the spinal dorsal horn (SDH) in mice following partial sciatic nerve ligation (PSL). Expression levels of neuroinflammatory molecules were evaluated by RT-qPCR and immunohistochemistry, and PSL-induced mechanical allodynia was defined by the von Frey test.ResultsFlow cytometry revealed that CD11b+ F4/80+ macrophages were accumulated in the injured sciatic nerve (SCN) after PSL. TC-2559, a full agonist for α4β2 nAChR, suppressed the upregulation of interleukin-1β (IL-1β) in the injured SCN after PSL and attenuated lipopolysaccharide-induced upregulation of IL-1β in cultured macrophages. Systemic (subcutaneous, s.c.) administration of TC-2559 during either the early (days 0-3) or middle/late (days 7-10) phase of PSL improved mechanical allodynia. Moreover, local (perineural, p.n.) administration of TC-2559 and sazetidine A, a partial agonist for α4β2 nAChR, during either the early or middle phase of PSL improved mechanical allodynia. However, p.n. administration of sazetidine A during the late (days 21-24) phase did not show the attenuating effect, whereas p.n. administration of TC-2559 during this phase relieved mechanical allodynia. Most importantly, p.n. administration of TC-2559 significantly suppressed morphological activation of Iba1+ microglia and decreased the upregulation of inflammatory microglia-dominant molecules, such as CD68, interferon regulatory factor 5, and IL-1β in the SDH after PSL.ConclusionThese findings support the notion that pharmacological inhibition of inflammatory macrophages using an α4β2 nAChR agonist exhibit a wide therapeutic window on neuropathic pain after nerve injury, and it could be nominated as a novel pharmacotherapy to relieve intractable pain.

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Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury.

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Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury.

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