Pain: How macrophages mediate inflammatory pain via ATP signaling

ArticleinNature Reviews Rheumatology 6(12):679-81 · December 2010with18 Reads
Impact Factor: 9.85 · DOI: 10.1038/nrrheum.2010.175 · Source: PubMed

Macrophages have important roles in the induction and resolution of inflammation, but the intracellular pathways from inflammatory signals to pain response remain unclear. A recent study demonstrates that the P2X4 receptor mediates inflammatory pain by inducing formation of the potent lipid mediator prostaglandin E2.

    • "Accordingly, we found in the present study that pharmacological inhibition and genetic depletion of TRPA1 reduced the production of several MSU crystalinduced chemokines and inflammatory cytokines as measured in the air-pouch model. Even though mechanisms related to TRPA1-triggered changes in gene expression are not fully understood , TRPA1-induced increase in intracellular Ca 2+ concentration may directly mediate the effect as changes in intracellular Ca 2+ levels are known to regulate the transcription of some inflammatory genes353637 . Against this background, our present findings, in which inhibition or depletion of TRPA1 significantly reduced edema formation and accumulation of proinflammatory cytokines and inflammatory cells in response to MSU crystals in synovial joint resembling subcutaneous air-pouch and in subcutaneous soft-tissue are reasonable and together with the results described recently [17,18] support the role of TRPA1 as a mediator of inflammatory responses in acute gouty arthritis. "
    [Show abstract] [Hide abstract] ABSTRACT: In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models. The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling. Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw. TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare.
    Full-text · Article · Feb 2015 · PLoS ONE
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    • "These data suggest that, in sensory ganglion culture, the development of a neuroinflammatory profile facilitates the release of endogenous mediators (including ATP and cytokines) to reinforce the activation of inflammatory cells and constitutively potentiates P2X3 receptors to amplify nociceptive signaling. Similar purinergic signaling likely occurs at central synapse, where block of ATP could represent a potential therapeutic target to limit microgliamediated inflammatory responses associated with chronic pain sensitization (Ulmann et al., 2008; Jakobsson, 2010 ). The possibility of ATP-mediated crosstalk also within ganglia has recently been proposed (Ceruti et al., 2008; Ohara et al., 2009; Belzer et al., 2010; Ceruti et al., 2011; Huang et al., 2013), supporting the intrinsic role of satellite glial cells for adaptation mechanisms during chronic pain (Hanani, 2012; Kung et al., 2013) and their role as inflammatory cells (van Velzen et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Increasing evidence indicates the importance of extracellular adenosine triphosphate (ATP) in the modulation of neuronal function. In particular, fine control of ATP release and the selective and discrete ATP receptor operation are crucial elements of the crosstalk between neuronal and non-neuronal cells in the peripheral and central nervous systems. In peripheral neurons, ATP signaling gives an important contribution to neuronal sensitization, especially that involved in neuropathic pain. Among other subtypes, P2X3 receptors expressed on sensory neurons are sensitive even to nanomolar concentrations of extracellular ATP, and therefore are important transducers of pain stimuli. P2X3 receptor function is highly sensitive to soluble factors like neuropeptides and neurotrophins, and is controlled by transduction mechanisms, protein-protein interactions and discrete membrane compartmentalization. More recent findings have demonstrated that P2X3 receptors interact with the synaptic scaffold protein calcium/calmodulin-dependent serine protein kinase (CASK) in a state dependent fashion, indicating that CASK plays a crucial role in the modulation of P2X3 receptor stability and efficiency. Activation of P2X3 receptors within CASK/P2X3 complex has important consequences for neuronal plasticity and possibly for the release of neuromodulators and neurotransmitters. Better understanding of the interactome machinery of P2X3 receptors and their integration with other receptors and channels on neuronal surface membranes, is proposed to be essential to unveil the process of neuronal sensitization and related, abnormal pain signaling.
    Full-text · Article · Dec 2013 · Frontiers in Cellular Neuroscience
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    • "However, in response to induced peripheral inflammation, mice lacking the P2 Â 4 receptor do not develop pain hypersensitivity and show a complete absence of inflammatory PGE2 in tissue exudates (Ulmann et al., 2010). The adverse side effects of non-steroidal anti-inflammatory drugs (NSAIDS) calls for the development of new anti-inflammatory drugs with analgesic properties, and so these findings suggest that targeting the macrophage-specific P2 Â 4 receptor could be a useful principle in treating the early stages of osteoarthritis and other inflammatory pain diseases (Jakobsson, 2010). Interestingly, microglia also express the same surface markers as macrophages, including P2 Â 4 receptors, ascribing multiple cellular targets to P2 Â 4 receptor blockade for alleviating inflammatory pain (Zhuo et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain.
    Full-text · Article · Sep 2013 · European Journal of Pharmacology
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