Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia

Banchet, Gisela Segond von; Boettger, Michael Karl; König, Christian; Iwakura, Yoichiro; Bräuer, Rolf; Schaible, Hans Georg

doi:10.1016/j.mcn.2012.11.006

Cited by 103 publications

(82 citation statements)

References 32 publications

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“…The surge in IL-17 has been found to increase with time, suggesting that it may be part of the chronic pain phase, rather than the initial period of injury and acute pain [78,79]. Administration of exogenous IL-17 results in neuropathic pain, possibly secondary to an increase in the activity of transient receptor protein vanilloid 4 (TRPV4), an ion channel that has been found to mediate mechanical allodynia [81,82]. By contrast, IL-17 knockout mice showed less response to pain after induced nerve injury [83], and anti-IL-17 antibody injection has been demonstrated to decrease pain in a murine model of arthritis [84].…”

Section: Targeting Pro-inflammatory Cytokinesmentioning

confidence: 99%

Targeting cytokines for treatment of neuropathic pain

Hung

Lim

Doshi

2017

Scandinavian Journal of Pain

149

120

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AbstractBackgroundNeuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options.MethodsA literature review was performed to assess the role of pro-inflammatory and antiinflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized.Results and conclusionsIn both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-α is perhaps the widely studied pro-inflammatory cytokine in the context of neuropathic pain, but other pro-inflammatory (IL-1β, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF-β) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition.

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Section: Targeting Pro-inflammatory Cytokinesmentioning

confidence: 99%

Targeting cytokines for treatment of neuropathic pain

Hung

Lim

Doshi

2017

Scandinavian Journal of Pain

149

120

View full text Add to dashboard Cite

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“…Receptors for these molecules are widely expressed by lumbar DRG neurons [36, 37], and incubation with IL-17A results in a rapid phosphorylation of PKB/Akt and ERK-1/2 in DRG neurons [36]. In addition, experiments on cultured DRG neurons revealed that IL-17 could produce increased expression of TRPV4, whereas TRPV1 was unaffected.…”

Section: Nociceptive Actions Of Cytokinesmentioning

confidence: 99%

“…In addition, experiments on cultured DRG neurons revealed that IL-17 could produce increased expression of TRPV4, whereas TRPV1 was unaffected. Reinforcing the possibility that TRPV4 may be important in mediating mechanical hyperalgesia, Il17a null mice showed protection against mechanical hyperalgesia, but not thermal hyperalgesia, in the zymosan inflammatory pain model [37]. …”

Section: Nociceptive Actions Of Cytokinesmentioning

confidence: 99%

Osteoarthritis joint pain: The cytokine connection

2014

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Osteoarthritis is a chronic and painful disease of synovial joints. Chondrocytes, synovial cells and other cells in the joint can express and respond to cytokines and chemokines, and all of these molecules can also be detected in synovial fluid of patients with osteoarthritis. The presence of inflammatory cytokines in the osteoarthritic joint raises the question whether they may directly participate in pain generation by acting on innervating joint nociceptors. Here, we first provide a systematic discussion of the known proalgesic effects of cytokines and chemokines that have been detected in osteoarthritic joints, including TNF-α, IL-1, IL-6, IL-15, IL-10, and the chemokines, MCP-1 and fractalkine. Subsequently, we discuss what is known about their contribution to joint pain based on studies in animal models. Finally, we briefly discuss limited data available from clinical studies in human osteoarthritis.

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“…A recent study showed that neuronal IL-17RA mediates IL-17A-induced up-regulation of transient receptor potential vanilloid 4 (TRPV4) in DRG neurons, suggesting that IL-17A is involved in mechanical hyperalgesia [32]. It has been reported that EA increased mechanical threshold in the CFAinduced inflammatory pain model [33].…”

Section: Fig (5)mentioning

confidence: 99%

Electroacupuncture Inhibits Spinal Interleukin-17A to Alleviate Inflammatory Pain in a Rat Model

Meng¹,

Lao²,

Shen³

et al. 2013

TOPAINJ

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Although acupuncture analgesia has been reported in clinical trials, its mechanisms have been unclear. It was recently reported that spinal astrocytes-produced interleukin-17A (IL-17A) facilitates inflammatory pain. Hypothesizing that electroacupuncture (EA) would suppress inflammation-enhanced IL-17A synthesis to inhibit pain, we induced hyperalgesia, as measured by decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, by subcutaneously injecting complete Freund's adjuvant (CFA, 0.08 ml, 40 µg Mycobacterium tuberculosis) into the hind paws of rats, or intrathecal (i.t.) IL-17A (400 ng in 10 µl) into the lumbar spinal cord. We then gave EA at acupoint GB30 for two 20-min periods, once immediately after CFA or IL-17A administration and again 2 h post-injection. For sham control, EA needles were inserted into GB30 without stimulation. PWL was measured before and 2.5 and 24 h after injection. Spinal IL-17A, IL-17 receptor A (IL-17RA), and phosphorylated NR1, an essential subunit of the N-methyl D-aspartate receptor (NMDAR), were determined 24 h post-CFA or -IL-17A using immunohistochemistry and western blot. Compared to sham control, EA inhibited CFA-caused thermal hyperalgesia 2.5 and 24 h post-CFA and concurrently suppressed inflammation-enhanced IL-17A and IL-17RA synthesis and NR1 phosphorylation in the ipsilateral spinal cord. EA inhibited IL-17A-produced thermal hyperalgesia, IL-17RA synthesis and NR1 phosphorylation. Our data suggest that EA inhibits inflammatory pain by blocking spinal IL-17A synthesis. Since previous study shows that IL-17A is located in astrocytes and IL-17RA and NR1 are in neurons, the data suggest that EA alleviates pain by modulating glia-neuronal interactions that involve IL-17A, IL-17RA, and NR1 phosphorylation.

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Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia

Cited by 103 publications

References 32 publications

Targeting cytokines for treatment of neuropathic pain

Targeting cytokines for treatment of neuropathic pain

Osteoarthritis joint pain: The cytokine connection

Electroacupuncture Inhibits Spinal Interleukin-17A to Alleviate Inflammatory Pain in a Rat Model

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