Littérature scientifique sur le sujet « Neuroimmune regulation »

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro–immuno–oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision.

Abstract The distal airway of the lung is innervated by vagus nerve. Upon stimulation, vagus nerve endings release acetylcholine or neuropeptides via C-fiber afferents to regulate lung infection and immunity. Vagal sensory nerve endings, brain integration center, acetylcholine and α7 nicotinic acetylcholine receptor (nAChR) expressing cells are key components of pulmonary parasympathetic inflammatory reflex. Meanwhile, this local machinery synergizes with spleen (as a functional hub of cholinergic anti-inflammatory pathway) to finely tune recruitment of the splenic α7 nAChR+CD11b+ cells into the inflamed lungs during lung infection. Recent studies have showed that lung group 2 innate lymphoid cells (ILC2) express both α7 nAChR and neuropeptide receptors. Acetylcholine and neuropeptides can regulate ILC2 and reshape pulmonary infection and immunity. Among the airway epithelial cells, pulmonary neuroendocrine cells are rare cell population; however, these cells are innervated by sensory nerve endings and they could secrete neuropeptides that influence lung infection and immunity.

Immune cells and immune-derived molecules, endocrine glands and hormones, the nervous system and neuro molecules form the combined tridirectional neuroimmune network, which plays a significant role in the communication pathways and regulation at the level of the whole organism and local levels, in both healthy persons and patients with allergic rhinitis based on an allergic inflammatory process. This review focuses on a new research paradigm devoted to neuronal-immune cell units, which are involved in allergic inflammation in the nose and neuroimmune control of the nasal mucociliary immunologically active epithelial barrier. The categorization, cellular sources of neurotransmitters and neuropeptides, and their prevalent profiles in constituting allergen tolerance maintenance or its breakdown are discussed. Novel data on the functional structure of the nasal epithelium based on a transcriptomic technology, single-cell RNA-sequencing results, are considered in terms of neuroimmune regulation. Notably, the research of pathogenesis and therapy for atopic allergic diseases, including recently identified local forms, from the viewpoint of the tridirectional interaction of the neuroimmune network and discrete neuronal-immune cell units is at the cutting-edge.

2012 - 2013
The human polyomavirus JC (JCV) is a small DNA virus responsible for the initiation of progressive multifocal leukoencephalopathy (PML), an often lethal disease of the brain characterized by lytic infection of oligodendrocytes in the central nervous system (CNS). Patients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired-immune system, most notably AIDS patients, are in the high risk group of developing PML. Previous studies suggested that soluble immune mediators secreted from PBMCs inhibited viral genomic replication. However little is known regarding the molecular mechanism of this regulation. Here we investigated the impact of conditioned media (CM) from activated PBMCs on viral replication and gene expression by molecular virology techniques. Our data showed that viral gene expression as well as viral replication was suppressed by the CM. Further studies revealed that soluble immune mediators from PBMCs possessed a dual control on T-antigen expression at transcription and post-transcription level. These observations demonstrate a novel role of immune mediators in regulation of JCV gene expression, and provide a new avenue of research to understand molecular mechanism of viral reactivation in patients who are at risk of developing PML. [edited by author]
XII n.s.

L’anandamide (arachidonoiletanolammide, AEA), insieme con l’altro endocannabinoide 2arachidonoilglicerolo (2-AG), lega ed attiva i due recettori accoppiati a proteine G inibitorie, (GPCR), chiamati recettori dei cannabinoidi di tipo-1 (CB1R) e di tipo-2 (CB2R). I CB1R sono localizzati principalmente nel sistema nervoso centrale, ma sono anche espressi in tessuti periferici come le cellule immunitarie. Mentre i CB2R sono maggiormente espressi a livello periferico, ma sono anche presenti nel cervello. Quindi l’attivazione dei recettori CB1 o CB2 da parte dell’AEA e del 2-AG ha molti effetti sia a livello centrale che periferico. Queste azioni sono controllate attraverso un non ancora caratterizzato meccanismo cellulare, che regola il rilascio degli endocannabinoidi da precursori di membrana, il loro trasporto all’interno delle cellule, ed infine la loro eliminazione. L’agente chiave nella sintesi dell’AEA è la N-acilfosfatidiletanolammine (NAPE)-fosfolipasi D (NAPE-PLD), mentre la sua degradazione avviene attraverso un trasportatore di membrana per AEA (AMT), ed una fatty acid amide hydrolase (FAAH). Oltre i recettori CB, l’AEA lega anche il recettore dei vanilloidi di tipo 1 (TRPV1). Il 2-AG è invece rilasciato da lipidi di membrana per azione di una lipasi specifica, sn-1-diacilglicerolo (DAGL), ed è idrolizzato da una specifica monoacilglicerolo lipasi (MAGL). E’ stato dimostrato che il trasporto del 2-AG attraverso la membrana cellulare è saturabile ed energia-indipendente e che può occorrere attraverso lo stesso trasportatore dell’AEA. L’AEA ed il 2-AG, con altri congeneri, le proteine che legano, trasportano, sintetizzano ed idrolizzano questi lipidi formano il “sistema endocannabinoide”. I lipid rafts sono subdomini della membrana plasmatica che contengono alte concentrazioni di colesterolo e di sfingolipidi, e sono ben conosciuti modulatori dell’attivitità di un numero di GPCR. Infatti, essi modulano il segnale ed il “trafficking” in molti tipi cellulari. La crescente evidenza che i lipid rafts possono modulare il segnale degli endocannabinoidi ci ha spinto ad investigare il possibile effetto della loro integrità sui recettori CB, sul metabolismo dell’AEA e del 2-AG in cellule neuronali e del sistema immunitario. A tale scopo abbiamo utilizzato la metil-β-ciclo destrina (MCD), un depletore del colesterolo, un composto largamente utilizzato per distruggere l’integrità dei lipid rafts. Abbiamo utilizzato le cellule di glioma di ratto C6, perché esse hanno un ben caratterizzato sistema endocannabinoide. Abbiamo poi esteso lo studio alla linea cellulare di neuroblastoma umano CHP100, la quale ha la stessa abilità delle cellule C6 di metabolizzare l’AEA, ma sono prive del CB1R e quindi sono più sensibili all’attività pro-apoptotica dell’AEA. Abbiamo inoltre esteso lo studio agli enzimi che degradano e sintetizzano il 2-AG. Inoltre, abbiamo studiato la linea cellulare umana DAUDI, perché possiede l’AMT e l’enzima FAAH ed esprime un CB2R funzionale. Le cellule DAUDI, inoltre, regolano importanti funzione in cui sono coinvolti i lipid rafts, come la secrezione di esosomi e l’arresto della crescita indotta dai farmaci antitumorali. Inoltre abbiamo valutato l’effetto della deplezione e dell’arrichimento di colesterolo sul metabolismo degli endocannabinoidi. In conclusione, questo studio ha monitorato l’effetto dell’integrità dei lipid rafts sulle principali proteine che legano e metabolizzano l’AEA ed il 2-AG, sia in cellule neuronali che in cellule del sistema immunitario. Tale studio indica che il CB1R ed il trasportatore degli endocannabinoidi sono probabilmente localizzati all’interno dei lipid rafts a differenza del CB2R e delle altre proteine che compongono il sistema endocannabinoide.
Anandamide (arachidonoylethanolamide, AEA) and the other endocannabinoid 2-arachidonoylglycerol (2-AG) bind to and activate two G protein-coupled receptors (GPCR), namely type-1 (CB1R) and type-2 (CB2R) cannabinoid receptors. CB1R are localized mainly in the central nervous system, but are also expressed in peripheral tissues like immune cells. Conversely CB2R are predominantly expressed peripherally, but they are also present in the brain. Therefore, activation of CB1 or CB2 receptors by AEA or 2-AG has many central and peripheral effects. These actions are controlled through not yet fully characterized cellular mechanisms, that regulate the release of endocannabinoids from membrane precursors, their uptake by cells, and finally their intracellular disposal. The key agent in AEA synthesis is the N-acylphosphatidylethanolamines (NAPE)-hydrolyzing phospholipase D (NAPE-PLD), whereas degradation occurs through an AEA membrane transporter (AMT), and a fatty acid amide hydrolase (FAAH). Besides CB receptors, AEA binds also to type 1 vanilloid receptors (now called transient receptor potential channel vanilloid receptor subunit 1, TRPV1). On the other hand, 2-AG is released from membrane lipids by means of a sn-1-specific diacylglycerol lipase (DAGL), and is hydrolyzed by a specific monoacylglycerol lipase (MAGL). The transport of 2-AG through the cellular membrane has been shown to be saturable and energyindependent, and might occur through the same AMT that transports AEA. Altogether AEA and 2-AG, with other congeners, the proteins that bind, transport, synthesize and hydrolyze these lipids, form the “endocannabinoid system”. Lipid rafts are subdomains of the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids, and are well-known modulators of the activity of a number of GPCR. In fact, they modulate signaling and membrane trafficking in many cell types. The growing evidence suggesting that lipid rafts might modulate the endocannabinoid signaling prompted us to investigate also the possible effect of lipid rafts integrity on CB receptors, on AEA metabolism in neuronal and immune cells and on the proteins that synthesize, transport and degrade 2-AG. We have used the methyl--cyclodextrin (MCD), a membrane cholesterol depletor that is widely used to disrupt the integrity of lipid rafts. We have chosen rat C6 glioma cells, because they have a well characterized endocannabinoid system. We extended the study to human CHP100 neuroblastoma cells, which have the same ability as C6 cells to metabolize AEA, but are devoid of CB1R and hence are more sensitive to the pro-apoptotic activity of AEA. We did not further extend this study to 2-AG and the enzymes that degrade and synthesize it, because 2-AG does not have pro-apoptotic activity toward C6 cells or CHP100 cells, in keeping with the observation that it does not activate TRPV1 receptors. Furthermore, we have chosen human DAUDI leukemia cells, because they have active AMT and FAAH, and express functional CB2R. On the other hand, in DAUDI cells lipid rafts regulate important functions like exosome secretion, or growth arrest induced by antitumor drugs. In addition, we checked for the first time the effect of membrane cholesterol depletion or enrichment on 2-AG metabolism in C6 cells and DAUDI cells. In conclusion, this study monitor the effect of lipid rafts integrity on all the major proteins that bind and metabolize AEA and 2-AG, both in neuronal and immune cells. The results point out that CB1R and endocannabinoid transporters are probably localized within lipid rafts, at variace with CB2R and the other proteins of the endocannabinoid system.

New neurons are added to the dentate gyrus of the hippocampus throughout adult life, through the process known as adult hippocampal neurogenesis (AHN). This important form of structural plasticity supports learning and memory in mammalian species. AHN is tightly regulated by a myriad of factors, including the immune system. Previous evidence suggests that signalling via Complement Component 3 (C3) and Complement C3a Receptor (C3aR) may regulate AHN under physiological conditions, although the mechanism of this putative regulation is unclear. In addition, C3a/C3aR signalling may regulate neuronal morphology. Using C3-/- and C3aR-/- mice, I used a combined in vitro and in vivo approach to investigate the role of C3/C3aR signalling in AHN. In Chapter 2, I demonstrate that C3a/C3aR signalling is able to directly influence hippocampal precursor cells in primary cultures. Furthermore, in the adult mouse brain, there is an increase in the number of immature neurons in the absence of C3 and C3aR, suggesting that C3a/C3aR signalling exerts an anti-neurogenic effect in the healthy brain. In Chapter 3 I report that the dendritic arborisation of newborn neurons is altered in the absence of C3aR, but not C3, suggesting involvement of an alternative ligand. Therefore, C3aR signalling via an as yet-unidentified ligand is important for maintaining the normal neuronal morphology of adult born neurons. Both the net levels of AHN and immature neuronal morphology have important functional consequences for cognitive and affective processes involving the hippocampus, which I investigate in Chapter 4. I report superior performance of C3-/- and C3aR-/- mice in a hippocampus-dependent spatial discrimination task, consistent with their elevated levels of AHN. Furthermore, C3a/C3aR deficiency was associated with abnormal anxiety phenotypes. In conclusion,these results demonstrate a novel mechanism for neuroimmune regulation of AHN, which is of functional consequence to learning, memory and affective behaviour.

Innate lymphoid cells (ILCs) are a lymphocyte subset which lack adaptive antigen-specific receptors, being the innate counterparts of T helper lymphocytes. ILCs act early in the immune response by producing effector cytokines in response to tissue-derived inducer cytokines. ILC2s, a subtype of ILCs, produce type 2 cytokines in response to helminthic infection, allergens, and epithelial injury. Besides their role in immune defense, ILC2s also contribute to metabolic homeostasis by maintaining an anti-inflammatory protective environment in the adipose tissue (AT). In obesity, excessive lipid accumulation results in chronic low-grade inflammation, causing a shift in immune cell populations that can lead to a systemic metabolic imbalance, known as metabolic syndrome. ILC2-derived molecules act on immune cells and on adipocytes, limiting obesity-induced inflammation and lipid accumulation, respectively. However, how ILC2s perceive environmental cues and integrate signals to maintain AT homeostasis remains poorly understood. Here, we hypothesize that neuroimmune interactions can control ILC2 function in the AT downstream from sympathetic nervous system innervation. Using pharmacological, genetic and imaging approaches, we show that AT ILC2s can integrate neuroregulatory molecules to control AT physiology.

Opioid drug abuse represents a serious public health concern with few effective therapeutic strategies. A primary goal for researchers modeling substance abuse disorders has been the delineation of the biological and environmental factors that shape an individual’s susceptibility or resistance to the reinforcing properties of abused substances. Early-life environmental conditions are frequently implicated as critical mediators for later-life health outcomes, although the cellular and molecular mechanisms that underlie these effects have historically been challenging to identify. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation in the nucleus accumbens (NAc), and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). The experiments described in this dissertation were thus designed to address if inflammatory signaling in the NAc may underlie the effects of early-life experience on later-life opioid drug-taking. The results demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug concentration-dependent manner. Transcriptional profiling of the NAc reveals a suppression of pro-inflammatory cytokine and chemokine signaling molecules and an increase in anti-inflammatory IL-10 in handled rats following repeated exposure to remifentanil. To directly test the hypothesis that anti-inflammatory signaling can alter drug-taking behavior, bilateral intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) or control pDNA were delivered into the NAc of naïve rats. pDNA-IL-10 treatment reduces remifentanil self-administration in a drug concentration-dependent manner, similar to the previous observations in handled rats. Additional experiments confirmed that neither handling nor pDNA-IL-10 treatment alters operant responding for food or sucrose rewards. These results help define the conditions under which ventral striatal neuroimmune signaling may influence motivated behaviors for highly reinforcing opioid drugs.

Dissertation