Divergent roles of immune cells and their mediators in pain

Raoof, Ramin; Willemen, Hanneke L.D.M.; Eijkelkamp, Niels

doi:10.1093/rheumatology/kex308

Cited by 100 publications

(79 citation statements)

References 158 publications

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“…A major source of endogenous cytokine production is from these resident and migratory DRG macrophages. In arthritic conditions (e.g., osteoarthritis and RA), macrophages infiltrate into the DRG and acquire a phenotype resembling that of TNF-stimulated macrophages, suggesting a role of these cells in the maintenance of arthritic pain (158). In vitro, macrophages stimulated with TNF promote release of calcitonin gene-related peptide (CGRP) by nociceptors, which is consistent with their pronociceptive effect (159).…”

Section: Dorsal Root Gangliamentioning

confidence: 77%

“…Intrathecally, coadministration of IFN-β and anti-TNF antibodies permanently reversed mechanical allodynia in males in the murine K/BxN serum transfer model of RA (41). Moreover, intrathecal delivery of cytokines such as TGF-β or IL-13 can also induce an antinociceptive effect in neuropathic pain condition (46,89,158). TGF-β can inhibit excitatory synaptic transmission in the spinal cord (172) and neuropathic pain along with glial activation and neuroinflammation in the spinal cord (89,172).…”

Section: Spinal Cordmentioning

confidence: 99%

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Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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Section: Dorsal Root Gangliamentioning

confidence: 77%

Section: Spinal Cordmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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“…While it is clear that peripheral immune cells migrate to local sites of nerve damage, a growing body of evidence supports that they also traffic to more remote pain-relevant neural tissues and play a role in the development of pathological pain. For instance, macrophages are recruited to sites remote from the initial insult, such as to the spinal cord (40,41) and DRG (41)(42)(43), following peripheral nerve trauma in response to chemotactic factors like CCL2 (42)(43)(44) and CX3CL1 (33,45) derived from injured neurons with their cell bodies or central projections in these distant locations. Macrophages present in the DRG are most likely important for maintenance of chronic pain.…”

Section: Macrophages In Pathological Painmentioning

confidence: 99%

Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management

2019

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Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

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“…Considering the role of the immune system in chronic inflammatory pain (Raoof et al, 2018), and the greater prevalence of chronic inflammatory pain in women than men (Unruh, 1996), research investigating sex differences in cytokines during chronic pain is needed. Sex differences in cytokine levels have been reported, but may be celland adjuvant-specific (reviewed in Klein and Flanagan, 2016).…”

Section: Introductionmentioning

confidence: 99%