Activité analgésique des lymphocytes T CD4+ dans les maladies inflammatoires chroniques de l'intestin

La sensation douloureuse est une caractéristique de la réponse inflammatoire qui accompagne les infections par des pathogènes ou les lésions tissulaires. Les médiateurs pro-inflammatoires libérés engendrent un message douloureux via la stimulation des fibres nerveuses sensitives primaires. Ce message douloureux est régulé in situ via la sécrétion d'opioïdes par les lymphocytes T CD4+ effecteurs générés en réponse au pathogène. Les propriétés analgésiques des lymphocytes T CD4+ sont acquises lors de leur activation par l'antigène dans les ganglions drainants via la synthèse de novo d'enképhalines. Les enképhalines sont ensuite libérées par les lymphocytes T CD4+ effecteurs lors de leur arrivée au site de l'inflammation, à la condition d'une nouvelle stimulation par l'antigène. Un défaut de régulation des lymphocytes T CD4+ de la muqueuse intestinale peut conduire au développement de maladies inflammatoires chroniques de l'intestin (MICI). Mes travaux de thèse ont montré chez la souris que les lymphocytes T CD4+ de phénotype Th1 ou Th17, caractéristiques des MICI, que l'on retrouve dans la muqueuse enflammée, produisent des enképhalines. L'utilisation de la technique de distension colorectale m'a permis de mettre en évidence qu'au cours de la phase aiguë de la colite, caractérisée par l'activation des cellules de l'immunité innée, les souris présentent une hypersensibilité viscérale. Celle-ci disparait dans la phase tardive de la maladie, lorsque les lymphocytes T infiltrent la muqueuse enflammée. Cette inhibition de l'hypersensibilité viscérale est dépendante de l'activation des récepteurs opioïdes périphériques par les enképhalines libérées localement par les lymphocytes. L'intensité de l'hypersensibilité viscérale apparait ainsi corrélée au taux d'infiltration de la muqueuse par les lymphocytes T plutôt qu'à l'étendue des dommages tissulaires. Cette observation nous a emmené à concevoir une nouvelle stratégie anti-nociceptive basée sur le recrutement des lymphocytes T dès la phase précoce de la colite. La stratégie que nous avons adoptée pour accélérer le recrutement des lymphocytes T sur le site inflammatoire, était basée sur la mise en place d'une réponse immunitaire secondaire. J'ai montré que l'immunisation préalable des souris permettait, lors d'une seconde exposition à l'antigène in situ, de réduire les douleurs viscérales inflammatoires. Cette stratégie analgésique était efficace dans les deux modèles de douleurs viscérales que j'ai étudiés, la colite induite par le DSS chez la souris, et la cystite interstitielle induite par le cyclophosphamide chez le rat. L'utilisation, lors de mon protocole, de vaccins couramment utilisés en médecine humaine permet d'envisager une application rapide chez l'homme.Painful sensation is a hallmark of the inflammatory response induced by the infection by pathogens or tissue damage. Pro-inflammatory mediators released during inflammation directly activate primary sensory neuron to initiate painful message. This painful message is regulated in situ via the secretion of opioids by effectors CD4+ T lymphocytes generated in response to the pathogen. The analgesic properties of the CD4+ T lymphocytes are acquired upon activation by antigen loaded-dendritic cells in the draining lymph nodes via the de novo synthesis of enkephalin. Enkephalins are released by effector CD4+ T lymphocytes upon their arrival at the site of inflammation after new antigen stimulation with the cognate antigen. A defective regulation of CD4 + T cells in the intestinal mucosa can lead to the development of inflammatory bowel disease (IBD). My work shows in mice that Th1 and Th17 effector CD4+ T lymphocytes that are associated with IBD produce enkephalins. Using colorectal distension, I demonstrate that, during the acute phase of colitis, characterized by the activation of innate immune cells, mice exhibit visceral hypersensitivity. This hypersensitivity disappears in the later stages of the disease, when T cells infiltrate the inflamed mucosa. This inhibition of visceral hypersensitivity is dependent on the activation of the peripheral opioid receptors by the local release of enkephalins by CD4+ T cells. The intensity of visceral hypersensitivity appears to correlate with the rate of infiltration of the mucosa by T cells rather than the extent of tissue damage. This observation led us to develop a new anti-nociceptive strategy based on the recruitment of T cells at the early phase of colitis. The strategy that we adopted to accelerate the recruitment of T cells to the site of inflammation, was based on the establishment of a secondary immune response. I showed immunization of mice allowed, during a second exposure of to the antigen in the inflammatory site, reduce inflammatory visceral pain. This analgesic strategy was effective in both models of visceral pain that I have studied, the DSS-induced colitis in mice, and the cyclophosphamide-induced interstitial cystitis in rats. The use, in my protocol, of vaccines commonly used in human medicine allows considering rapid application in humans

TRPV1 promotes opioid analgesia during inflammation

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5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca2+ imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)- and pertussis toxin-dependent mechanism, suggesting that the effect was mediated by a G protein-coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.BBSRC BB/R006210/1 to James R F Hockley and Ewan St John Smith Rosetrees 834 Postdoctoral Grant (A1296) awarded to James R F Hockley and Ewan St John Smit

Mas-related G protein-coupled receptors (Mrgprs) – Key regulators of neuroimmune interactions

International audienceInterplay between physiological systems in the body plays a prominent role in health and disease. At the cellular level, such interplay is orchestrated through the binding of specific ligands to their receptors expressed on cell surface. G protein-coupled receptors (GPCR) are seven-transmembrane domain receptors that initiate various cellular responses and regulate homeostasis. In this review, we focus on particular GPCRs named Mas-related G protein-coupled receptors (Mrgprs) mainly expressed by sensory neurons and specialized immune cells. We describe the different subfamilies of Mrgprs and their specific ligands, as well as recent advances in the field that illustrate the role played by these receptors in neuro-immune biological processes, including itch, pain and inflammation in diverse organs

Visualização de trajetórias utilizando o Visualization Toolkit

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Visualização de trajetórias utilizando o Visualization Toolkit

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Delta opioid receptors on nociceptive sensory neurons mediate peripheral endogenous analgesia in colitis

International audienceAbstract Background Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4 + T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia. Methods The peripheral analgesia associated with the accumulation of CD4 + T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Na v 1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model. Results Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa. Conclusion The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders