Sex-distinct microglial activation and myeloid cell infiltration in the spinal cord after painful peripheral injury.

Autor:	Huck NA; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Donovan LJ; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Shen H; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA.; Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou 215000, China., Jordan CE; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Muwanga GPB; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA.; Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA., Bridges CM; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Forman TE; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Cordonnier SA; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Haight ES; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Dale-Huang F; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA., Takemura Y; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA.; Department of Anesthesiology, University of Toyama, Toyama 930-0194, Japan., Tawfik VL; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA 94305, USA.
Jazyk:	angličtina
Zdroj:	Neurobiology of pain (Cambridge, Mass.) [Neurobiol Pain] 2022 Oct 12; Vol. 12, pp. 100106. Date of Electronic Publication: 2022 Oct 12 (Print Publication: 2022).
DOI:	10.1016/j.ynpai.2022.100106
Abstrakt:	Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex in situ hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2022 The Authors.)
Databáze:	MEDLINE
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