Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice

Kuhn, Julia; Vainchtein, Ilia D.; Bráz, Joao; Hamel, Katherine; Bernstein, Mollie; Craik, Veronica; Dahlgren, Madelene W; Ortiz-Carpena, Jorge F.; Molofsky, Ari B.; Molofsky, Anna V.; Basbaum, Allan I.

doi:10.7554/elife.69056

Cited by 64 publications

(57 citation statements)

References 59 publications

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Section: Neuroimmune Interfaces Within the Central Nervous Systemmentioning

confidence: 99%

“…158 Meningeal Tregs in females are capable of interacting with spinal cord microglia to suppress the microglia-dependent pathway for pain hypersensitivity. 173 Sexual dimorphism in pain is a fascinating area of research, and current preclinical studies span beyond T cell and microglia function and implicate other neuroimmune players, such as myeloid cells and even neurons themselves. 51,174 Neuron and T Lymphocyte Interactions T cells respond to neuronal outputs as they express receptors including ionotropic and metabotropic glutamate receptors, CGRP receptors, and neurokinin-1 (NK1) receptors.…”

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confidence: 99%

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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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Section: Neuroimmune Interfaces Within the Central Nervous Systemmentioning

confidence: 99%

mentioning

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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“…Multiple studies have indicated that the local microenvironment plays an important role in regulating the microglial phenotype [39][40][41][42][43][44]. Microglial activation can be initiated by injured neurons [45][46][47][48], which contributes to central nervous system (CNS) pathology, such as in models of neuropathic pain [22,46,[48][49][50][51][52]. A recent study showed that impaired death (necroptosis) and/or repopulation of microglia underpin their dysregulated activation in neurological diseases [53]; in addition, necroptosis can be triggered by many death receptors, including Fas, TRAIL and TNF receptors, mainly through the signalling pathway induced via the binding of TNF-α to TNF receptor 1 (TNFR1) [54].…”

Section: Introductionmentioning

confidence: 99%

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

Duan

Chen

et al. 2022

IJMS

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The neuroimmune mechanism underlying neuropathic pain has been extensively studied. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine that drives cytokine storm and stimulates a cascade of other cytokines in pain-related pathways, induces and modulates neuropathic pain by facilitating peripheral (primary afferents) and central (spinal cord) sensitization. Functionally, TNF-α controls the balance between cell survival and death by inducing an inflammatory response and two programmed cell death mechanisms (apoptosis and necroptosis). Necroptosis, a novel form of programmed cell death, is receiving increasing attraction and may trigger neuroinflammation to promote neuropathic pain. Chronic pain is often accompanied by adverse pain-associated emotional reactions and cognitive disorders. Overproduction of TNF-α in supraspinal structures such as the anterior cingulate cortex (ACC) and hippocampus plays an important role in pain-associated emotional disorders and memory deficits and also participates in the modulation of pain transduction. At present, studies reporting on the role of the TNF-α–necroptosis pathway in pain-related disorders are lacking. This review indicates the important research prospects of this pathway in pain modulation based on its role in anxiety, depression and memory deficits associated with other neurodegenerative diseases. In addition, we have summarized studies related to the underlying mechanisms of neuropathic pain mediated by TNF-α and discussed the role of the TNF-α–necroptosis pathway in detail, which may represent an avenue for future therapeutic intervention.

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“…Multiple mechanisms underlying sex differences in pain experience, lower tolerance to pain in females and sexually dimorphic efficacy of drug intervention have been either hypothesized or demonstrated. For instance, sex affects the response of the immune system, as shown by the role of the adaptive immune system and higher infiltration of cluster of differentiation 4 (CD4)+ T-lymphocytes after peripheral nerve injury [ 30 ], or regarding the contribution of regulatory T-cells (Tregs)-mediated suppression of microglia activation as well as the alteration of macrophage activities and pain hypersensitivity in female mice [ 31 ]. We also investigated sex differences in NeP, providing evidence that microglia homeostasis follows in female mice a different temporal pattern of activation after peripheral nerve lesion (i.e., chronic constriction injury, CCI), with a late and persistent glial cells activation and incomplete functional recovery [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin

Angelis

Vacca

Tofanicchio

et al. 2022

IJMS

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As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This “gender gap” in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the “gender gap” problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.

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Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice

Cited by 64 publications

References 59 publications

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

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

Neuroimmune Mechanisms Underlying Neuropathic Pain: The Potential Role of TNF-α-Necroptosis Pathway

Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin

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