A spinal microglia population involved in remitting and relapsing neuropathic pain

Kohno, Keita; Shirasaka, Ryoji; Yoshihara, Kohei; Mikuriya, Satsuki; Tanaka, Kaori; Takanami, Keiko; Inoue, Kazuhide; Sakamoto, Hirotaka; Ohkawa, Yasuyuki; Masuda, Takahiro; Tsuda, Makoto

doi:10.1126/science.abf6805

Cited by 139 publications

(89 citation statements)

References 43 publications

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“…But if R406 acts to induce microglia, or a subset thereof, to produce a pain-reducing signal then microglia could be the cell type in which R406 acts. Recently, a subtype of microglia, expressing cd11c, was reported to actively reverse hypersensitivity ( 30 ) in both sexes raising the possibility that R406 may act on this microglia subtype which strongly expresses Syk and for which the molecular signature gene, Itgax, is in the SNI-induced pain interactome (Fig. 5D).…”

Section: Discussionmentioning

confidence: 99%

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Ghazisaeidi

Muley

et al. 2022

Preprint

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Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.

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Section: Discussionmentioning

confidence: 99%

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Ghazisaeidi

Muley

et al. 2022

Preprint

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“…Our structural, functional and in tissue analyses further demonstrate that acentrosomal MT nucleation at Golgi outposts may play an important role in supporting the patrolling phenotype of microglia cells, that tubulin remodeling enables microglia reactivity in vitro and in tissue, and that targeting PCM maturation in reactive microglia may represent a new approach to limit tissue damage during neurodegenerative disease in which microgliosis contributes to neuronal injury and cognitive decline 2, 12 . In addition, given the newly identified role for a population of spinal CD11c + microglia in the remission and recurrence of neuropathic pain 95 , it will be become critical to determine the contribution of spinal microglial MT dysfunction in the peripheral neuropathy caused by chemotherapeutic drugs, most of which target the MT cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays

Rosito¹,

Sanchini²,

Gosti³

et al. 2022

Preprint

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Microglia reactivity triggered by proinflammatory signaling entails a large-scale remodeling of cellular geometry, but the role of the microtubule cytoskeleton during these changes remains unexplored. Here we show that reactive proinflammatory microglia provide a heretofore unique example of microtubule reorganization from a non-centrosomal array of parallel and stable microtubules to a radial array of more dynamic microtubules. While in the homeostatic state microglia nucleate microtubules at Golgi outposts, proinflammatory signaling induces recruitment of nucleating material nearby the centrosome and inhibition of de novo formed pericentrosomal microtubule-organizing centers enhances NLRP3 inflammasome activation and secretion of the interleukin IL-1β. Our results demonstrate that remodeling of the microtubule cytoskeleton is a hallmark of proinflammatory microglia reactivity and suggest that pericentrosomal microtubule nucleating material maturation may offer a valuable target to modulate cytokine-mediated inflammatory responses in chronic disease and tissue injury.

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“…[28][29][30] The microglia-neuron interface is implicated in the pathogenesis of many brain diseases including chronic pain and is one of the most studied CNS neuroimmune interfaces. 16,[31][32][33][34][35] Clinical correlation of the microglia-neuronal interface is largely absent despite much work in preclinical models of chronic pain. The inability to identify the microglia-neuron interface clinically is a major limitation, let alone to follow how this interface changes over the course of chronic pain.…”

Section: Neuroimmune Interfaces Within the Central Nervous Systemmentioning

confidence: 99%

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

Su¹,

Zhang²,

He³

et al. 2022

JPR

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Chronic pain remains a public health problem and contributes to the ongoing opioid epidemic. Current pain management therapies still leave many patients with poorly controlled pain, thus new or improved treatments are desperately needed. One major challenge in pain research is the translation of preclinical findings into effective clinical practice. The local neuroimmune interface plays an important role in the initiation and maintenance of chronic pain and is therefore a promising target for novel therapeutic development. Neurons interface with immune and immunocompetent cells in many distinct microenvironments along the nociceptive circuitry. The local neuroimmune interface can modulate the activity and property of the neurons to affect peripheral and central sensitization. In this review, we highlight a specific subset of many neuroimmune interfaces. In the central nervous system, we examine the interface between neurons and microglia, astrocytes, and T lymphocytes. In the periphery, we profile the interface between neurons in the dorsal root ganglion with T lymphocytes, satellite glial cells, and macrophages. To bridge the gap between preclinical research and clinical practice, we review the preclinical studies of each neuroimmune interface, discuss current clinical treatments in pain medicine that may exert its action at the neuroimmune interface, and highlight opportunities for future clinical research efforts.

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A spinal microglia population involved in remitting and relapsing neuropathic pain

Cited by 139 publications

References 43 publications

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

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