It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. Here we show that TRPA1 is also expressed in Schwann cells. We found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Activation of Schwann cell TRPA1 evoked NADPH oxidase 1 (NOX1)-dependent H2O2 release, and silencing or blocking Schwann cell NOX1 attenuated nerve injury-induced macrophage infiltration, oxidative stress and allodynia. Furthermore, the NOX2-dependent oxidative burst, produced by macrophages recruited to the perineural space activated the TRPA1–NOX1 pathway in Schwann cells, but not TRPA1 in nociceptors. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia.

Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by TRPA1) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type (Trpa1(+/+)) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice (P < 0.05-P < 0.001). Both genetic deletion of Trpa1 (Trpa1(-/-)) and pharmacological blockade (HC-030031 and A-967079) abrogated pain-like behaviours (both P < 0.001), which were abated by the antioxidant, α-lipoic acid, and the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin (both P < 0.001). Nociception and hypersensitivity evoked by constriction of the infraorbital nerve was associated with intra- and perineural monocytic and macrophagic invasion and increased levels of oxidative stress by-products (hydrogen peroxide and 4-hydroxynonenal). Attenuation of monocyte/macrophage increase by systemic treatment with an antibody against the monocyte chemoattractant chemokine (C-C motif) ligand 2 (CCL2) or the macrophage-depleting agent, clodronate (both P < 0.05), was associated with reduced hydrogen peroxide and 4-hydroxynonenal perineural levels and pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, α-lipoic acid or the anti-CCL2 antibody (all P < 0.001). The present findings propose that, in the constriction of the infraorbital nerve model of trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by-products released from monocytes and macrophages clumping at the site of nerve injury.

A complex network of many interacting mechanisms orchestrates immune and inflammatory responses. Among these, the cation channels of the transient receptor potential (TRP) family expressed by resident tissue cells, inflammatory and immune cells and distinct subsets of primary sensory neurons, have emerged as a novel and interrelated system to detect and respond to harmful agents. TRP channels, by means of their direct effect on the intracellular levels of cations and/or through the indirect modulation of a large series of intracellular pathways, orchestrate a range of cellular processes, such as cytokine production, cell differentiation and cytotoxicity. The contribution of TRP channels to the transition of inflammation and immune responses from a defensive early response to a chronic and pathological condition is also emerging as a possible underlying mechanism in various diseases. This review discusses the roles of TRP channels in inflammatory and immune cell function and provides an overview of the effects of inflammatory and immune TRP channels on the pathogenesis of human diseases.Abbreviations ADPR, ADP ribose; APC, antigen presenting cell; BMMCs, bone marrow-derived mast cells; cADPR, cyclic ADPR; COPD, chronic obstructive pulmonary disease; CRAC, Ca 2+ -release activated channel; DCs, dendritic cells; EAE, experimental autoimmune encephalomyelitis; fMLP, fMet-Leu-Phe peptide; MCs, mast cells; NAADP, nicotinic acid adenine dinucleotide phosphate; NOX, NADPH oxidase; ORAI1, Ca 2+ -release-activated Ca 2+ channel protein 1; PMNs, polymorphonuclear neutrophil granulocytes; SOCE, store-operated calcium entry; STIM1, stromal interaction molecule 1; TCR, T-cell receptor Tables of Links TARGETS Voltage-gated Ion Channels TRPM1 TRPV1 TRPA1 TRPM2 TRPV2 TRPC1 TRPM4 TRPV4 TRPC3 TRPM5 TRPV5 TRPC5 TRPM7 TRPV6 TRPC6 TRPM8 Dendritic cellsDendritic cells (DCs), the most efficient APCs, are the first orchestrators of the immune response, given that they patrol the environment throughout the body and determine whether and how an immune response should be initiated (Lipscomb and Masten, 2002). DCs are specifically able to process, interpret and, finally, communicate the nature of the pathogenic stimulus to initiate all antigen-driven immune responses (Banchereau and Steinman, 1998). DCs capture and process pathogenic antigens, express costimulatory molecules that are able to enhance the T-cell response, secrete stimulatory cytokines and are involved in the maintenance of the immune tolerance (the ability of immune system to not produce immune responses against self-antigens or non-pathogenic environmental antigens) (Mellman, 2013). Pathogenic stimuli switch immature DCs, adept at antigen accumulation, to mature DCs, specialized for T-cell stimulation, which express a high level of antigen-presenting and co-stimulatory molecules and cytokines, and migrate to lymph nodes. PMNsPMNs are key players in inflammatory processes. Monocytes and macrophagesMacrophages and their precursors, monocytes, have ...

Glyceryl trinitrate administration causes prolonged mechanical allodynia in rodents, which correlates temporally with delayed migraine attacks in patients. Marone et al. show that the allodynia is mediated by TRPA1 activation in cell bodies of trigeminal neurons and ensuing oxidative stress. This neuronal pathway may be of relevance to migraine-like headaches.

Background and Purpose Stress‐related catecholamines have a role in cancer and β‐adrenoceptors; specifically, β2‐adrenoceptors have been identified as new targets in treating melanoma. Recently, β3‐adrenoceptors have shown a pleiotropic effect on melanoma micro‐environment leading to cancer progression. However, the mechanisms by which β3‐adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub‐population homeostasis. Understanding the mechanisms of cancer immune‐tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β3‐adrenoceptors in immune‐tolerance regulation. Experimental Approach A mouse model of melanoma in which syngeneic B16‐F10 cells were injected in C57BL‐6 mice was used to evaluate the effect of β‐adrenoceptor blockade on the number and activity of immune cell sub‐populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β‐blockers (propranolol and SR59230A) and specific β‐adrenoceptor siRNAs targeting β2‐ or β3‐adrenoceptors were used. Key Results Only β3‐, but not β2‐adrenoceptors, were up‐regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub‐populations including Treg, MDSC, and NK. SR59230A and β3‐adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub‐populations in the tumour mass, blood, and spleen. SR59230A and β3‐adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. Conclusions and Implications Our data suggest that β3‐adrenoceptors are involved in immune‐tolerance, which opens the way for new strategic therapies to overcome melanoma growth. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc