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Intestinal neuro-immune interactions. a Microbial commensals tune intestinal peristalsis by shaping the bidirectional communication among CSF1-producing enteric neurons and BMP2-producing MMs. Activation of extrinsic sympathetic ganglia by bacteria drives the polarization of ?2AR-expressing MMs into a tissue-protective phenotype. b EGC sense microbiota-derived cues to control GFLs expression. ECG-derived GFLs activate RET-expressing ILC3s, which induces IL-22 that ultimately controls intestinal homeostasis. c Cholinergic enteric neurons sense and respond to worm products by producing the neuropeptide NMU. Neuronal-derived NMU induces an immediate activation of NMUR1-expressing ILC2s that contributes to a protective immune response against parasitic infections. CSF1 colony-stimulating factor 1, Mo monocyte, BMP2, bone morphogenetic protein 2, NE norepinephrine, Arg1 encodes the arginase 1 protein, Chi3l3 encodes the chitinaselike protein 3, GFLs, glial cell line-derived neurotrophic factor family ligands, IL interleukin, ILC innate lymphoid cell, NMU neuromedin U
Source publication
Mucosal barriers constitute major body surfaces that are in constant contact with the external environment. Mucosal sites are densely populated by a myriad of distinct neurons and immune cell types that sense, integrate and respond to multiple environmental cues. In the recent past, neuro-immune interactions have been reported to play central roles...
Contexts in source publication
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... cross-talk The intestine also contains a vast reservoir of macrophages, most of which locate in the lamina propria and in the muscularis externa. 46 Recently, two independent studies reported that muscularis macrophages (MMs) can establish a bidirectional interplay with mucosal neurons 47,48 ( Fig. 2a). Muller et al. 48 demonstrated that MMs can regulate homeostatic GI ...
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... In agreement, infection with Salmonella typhimurium activates extrinsic tyr- osine hydroxylase-expressing neurons in the sympathetic gang- lia, with consequent norepinephrine release in the intestinal muscularis. 47 In turn, norepinephrine activation of β2AR- expressing MMs drives their polarization towards a tissue- protective phenotype 47 (Fig. ...
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... or pathogen-associated molecular patterns (PAMPs). 49,50 ILC2s rather sense barrier disruption by integrating locally produced host-derived signals, including alarmins, lipid mediators and neuropeptides. 49,50 Three recent independent studies reported that mucosal neurons can directly regulate innate type 2 immunity via neuromedin U (NMU) 51-53 (Fig. 2c). Analysis of the ILC transcriptome revealed that ILC2s selectively express NMU receptor 1 (Nmur1), which encodes the peripheral receptor of the neuropeptide NMU. 51-53 NMU is a highly conserved neuropeptide, mostly expressed in the GI tract and the CNS. 54 Intestinal ILC2s were found in close proximity to NMU-expressing cholinergic ...
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... Analysis of the ILC transcriptome revealed that ILC2s selectively express NMU receptor 1 (Nmur1), which encodes the peripheral receptor of the neuropeptide NMU. 51-53 NMU is a highly conserved neuropeptide, mostly expressed in the GI tract and the CNS. 54 Intestinal ILC2s were found in close proximity to NMU-expressing cholinergic neurons 51,52 (Fig. ...
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... in response to N. brasiliensis excretory/secretory products in a myeloid differentiation primary response 88 (MYD88)-dependent manner. 51 Taken together, these studies uncover a novel layer of homeostatic regulation whereby mucosal cholinergic neurons sense pathogen-derived molecules that induce NMU production and consequent activation of ILC2s (Fig. 2c). Adding to the neuronal regulation of ILC2 responses, catecho- laminergic neurons, a sympathetic nervous system component, were shown to impair innate type 2 responses. 55 Catecholami- nergic neurons are a source of norepinephrine that binds the β2AR. 5 β2AR deficiency leads to increased ILC2 responses, while β2AR agonist treatment led ...
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... were shown to impair innate type 2 responses. 55 Catecholami- nergic neurons are a source of norepinephrine that binds the β2AR. 5 β2AR deficiency leads to increased ILC2 responses, while β2AR agonist treatment led to deficient ILC2 responses and impaired inflammation, indicating that neuronal-derived signals can limit type 2 inflammation 55 (Fig. ...
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... mice with RET-deficient ILC3s displayed a poor epithelial reactivity that was associated with exacerbated dextran sulphate sodium-induced intestinal inflammation and increased susceptibility to Citrobacter rodentium infection. 76 GFL- producing EGCs were found in close association with ILC3s, suggesting a paracrine EGC-ILC3 interaction 76 (Fig. 2b). Astonish- ingly, microbial products and host-derived alarmins regulate glial- derived GFL expression in an MYD88-dependent manner. 76 Notably, glial cell-specific deletion of MYD88 signalling impaired GFL and innate IL-22 expression and increased susceptibility to intestinal inflammation and infection. 76 In conclusion, glial cells ...
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... glial cell-specific deletion of MYD88 signalling impaired GFL and innate IL-22 expression and increased susceptibility to intestinal inflammation and infection. 76 In conclusion, glial cells translate microbial and host-derived alarmin cues into GFL production, which then target neuronal and ILC3 function to promote intestinal homeostasis (Fig. ...
Citations
... Moreover, we showed that histamine sensitized murine trigeminal ganglionic neurons for capsaicin and cinnamaldehyde (Figure 4). The mast cell mediator histamine was shown to sensitize dorsal root ganglionic neurons for capsaicin and cinnamaldehyde in the context of irritable bowel syndrome or detrusor overactivity (27)(28)(29)35) . Considering NHR in AR or CRSwNP, one cannot only speak of upregulation of nociceptor expression, but also of neurogenic sensitization, at least in murine neurons. ...
Background:
Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation.
Methods:
Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons.
Results:
CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/ patients (p.
... In response, the brain, through the efferent vagus nerve, suppresses the production of pro-inflammatory cytokines, especially TNFα. It is also known that neurons express membrane receptors for cytokines and other molecules produced by immune cells [134][135][136][137], as well as pattern recognition receptors that allow them to directly respond to microbial signals [138][139][140][141]. On the other hand, immune cells are not only able to respond to neurotransmitters and neuropeptides through their receptors, but some of them also possess the capacity to produce and metabolize neurotransmitters [138,139,142,143]. The gastrointestinal tract is controlled by a complex network of nerves, including the intrinsic enteric nervous system (ENS) and the extrinsic sympathetic, parasympathetic, and visceral afferent neurons [144]. ...
The gastrointestinal (GI) tract of multicellular organisms, especially mammals, harbors a symbiotic commensal microbiota with diverse microorganisms including bacteria, fungi, viruses, and other microbial and eukaryotic species. This microbiota exerts an important role on intestinal function and contributes to host health. The microbiota, while benefiting from a nourishing environment, is involved in the development, metabolism and immunity of the host, contributing to the maintenance of homeostasis in the GI tract. The immune system orchestrates the maintenance of key features of host–microbe symbiosis via a unique immunological network that populates the intestinal wall with different immune cell populations. Intestinal epithelium contains lymphocytes in the intraepithelial (IEL) space between the tight junctions and the basal membrane of the gut epithelium. IELs are mostly CD8+ T cells, with the great majority of them expressing the CD8αα homodimer, and the γδ T cell receptor (TCR) instead of the αβ TCR expressed on conventional T cells. γδ T cells play a significant role in immune surveillance and tissue maintenance. This review provides an overview of how the microbiota regulates γδ T cells and the influence of microbiota-derived metabolites on γδ T cell responses, highlighting their impact on immune homeostasis. It also discusses intestinal neuro-immune regulation and how γδ T cells possess the ability to interact with both the microbiota and brain.
... Substantial bidirectional communication between the enteric neurons and immune cells has been established in both healthy and disease states, emphasizing the significance of ENS in GI immunity [11][12][13][14]. The ENS comprises an interconnected network of enteric neurons and glial cells within the GI tract projecting towards effector structures, such as smooth muscular layers, immune cells, and blood vessels [15]. ...
Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD.
... An enrichment analysis within the module with the highest correlation with total IgE (turquoise) supports neuroimmune coregulation of this trait. 54,55 ...
... In mammals, sensory neurons at mucosal barriers are heavily studied because of their close proximity to pathogens, their ability to transmit pathogen signals from the periphery to the brain, and their potent immune regulatory functions. As such, sensory neurons found at mammalian mucosal barriers are the target of therapeutic interventions from pain and itch to infectious diseases (Chesné et al., 2019 ;Godinho-Silva et al., 2019 ;Huh and Veiga-Fernandes, 2020 ;Pinho-Ribeiro et al., 2017 ). ...
Olfactory sensory neurons (OSNs) are constantly exposed to pathogens, including viruses. However, serious brain infection via the olfactory route rarely occurs. When OSNs detect a virus, they coordinate local antiviral immune responses to stop virus progression to the brain. Despite effective immune control in the olfactory periphery, pathogen-triggered neuronal signals reach the CNS via the olfactory bulb (OB). We hypothesized that neuronal detection of a virus by OSNs initiates neuroimmune responses in the OB that prevent pathogen invasion. Using zebrafish (Danio rerio) as a model, we demonstrate viral-specific neuronal activation of OSNs projecting into the OB, indicating that OSNs are electrically activated by viruses. Further, behavioral changes are seen in both adult and larval zebrafish after viral exposure. By profiling the transcription of single cells in the OB after OSNs are exposed to virus, we found that both microglia and neurons enter a protective state. Microglia and macrophage populations in the OB respond within minutes of nasal viral delivery followed decreased expression of neuronal differentiation factors and enrichment of genes in the neuropeptide signaling pathway in neuronal clusters. Pituitary adenylate-cyclase-activating polypeptide (pacap), a known antimicrobial, was especially enriched in a neuronal cluster. We confirm that PACAP is antiviral in vitro and that PACAP expression increases in the OB 1 day post-viral treatment. Our work reveals how encounters with viruses in the olfactory periphery shape the vertebrate brain by inducing antimicrobial programs in neurons and by altering host behavior.
... 54 In addition, such neuroimmune circuits are key orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, host defense, inflammation, tissue repair, metabolism, and thermogenesis. 1,2,143,144 Different branches of the PNS, including the sensory, sympathetic, parasympathetic, and enteric nervous systems have been shown to form neuroimmune hubs, mostly with innate immune cells. Although peripheral neuroimmune cell interactions have been extensively reviewed elsewhere, 1,2,143,144 here our goal is to provide examples of neuroimmune interactions by macrophages and ILCs, which highlight the potential impact of neuroimmune regulation of cardiovascular health and disease. ...
The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit-derived and heart-brain circuit-derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.
... In mammals, sensory neurons at mucosal barriers are heavily studied because of their close proximity to pathogens, their ability to transmit pathogen signals from the periphery to the brain, and their potent immune regulatory functions. As such, sensory neurons found at mammalian mucosal barriers are the target of therapeutic interventions from pain and itch to infectious diseases (Chesné et al., 2019;Godinho-Silva et al., 2019;Huh and Veiga-Fernandes, 2020;Pinho-Ribeiro et al., 2017). ...
Olfactory sensory neurons (OSNs) are constantly exposed to pathogens, including viruses. However, serious infection of the brain by the olfactory route rarely occurs. When OSNs detect a virus, they coordinate local antiviral immune responses to stop virus progression into the brain. Despite effective immune control at the olfactory periphery, pathogen-triggered neuronal signals reach the CNS via initial outputs in the olfactory bulb (OB). We hypothesized that neuronal detection of a virus by OSNs initiates neuroimmune responses in the OB that prevent pathogen invasion. Using zebrafish (Danio rerio) as a model, we demonstrate viral-specific neuronal activation of OSNs projecting into the OB, indicating that OSNs are electrically activated by viruses. Further, behavioral changes are seen in both adult and larval zebrafish after viral exposure. By profiling the transcription of single cells in the OB after OSNs are exposed to virus, we found that both microglia and neurons enter a protective state. Cells with microglia and macrophage markers in the OB respond within minutes of nasal viral delivery followed by striking responses in neuronal clusters characterized by decreased expression of neuronal differentiation factors and enrichment of genes in the neuropeptide signaling pathway, especially the known antimicrobial pacap. We confirm that PACAP is antiviral in vitro and that PACAP expression increases in the OB 1 day post-viral treatment. Our work reveals how encounters with viruses in the olfactory periphery shape the vertebrate brain by inducing antimicrobial programs in neurons and by altering host behavior.
... These secreted cytokines can be detected in the peripheral nervous system and affect innate immune cells in the brain by providing feedback via neuroimmune circuits [35]. In parallel, CCL5/CCR5 axis potentiation can 21:196 lead to superfluous infiltration of inflammatory cells into lesions, which promotes widespread molecular crosstalk between central and peripheral immune cells following BBB disruption [36]. Double immunofluorescence also revealed that the number of infiltrated monocytes around the hematoma was increased, although quantitative data is lacking. ...
Background
Owing to metabolic disequilibrium and immune suppression, intracerebral hemorrhage (ICH) patients are prone to infections; according to a recent global analysis of stroke cases, approximately 10 million new-onset ICH patients had experienced concurrent infection. However, the intrinsic mechanisms underlying the effects of infection related peripheral inflammation after ICH remain unclear.
Methods
Lipopolysaccharide (LPS) was intraperitoneally injected into ICH model mice to induce peripheral inflammation. Neurobehavioral deficits, blood‒brain barrier (BBB) disruption, and the expression of CCR5, JAK2, STAT3, and MMP9 were evaluated after treatment with recombinant CCL5 (rCCL5) (a CCR5 ligand), maraviroc (MVC) (an FDA-approved selective CCR5 antagonist), or JAK2 CRISPR plasmids.
Results
Our study revealed that severe peripheral inflammation increased CCL5/CCR5 axis activation in multiple inflammatory cell types, including microglia, astrocytes, and monocytes, and aggravated BBB disruption and neurobehavioral dysfunction after ICH, possibly in part through the JAK2/STAT3 signaling pathway.
Conclusions
CCR5 might be a potential target for the clinical treatment of infection-induced exacerbation of BBB disruption following ICH.
... It is believed that gut bacteria can affect PD through both indirect and direct pathways via the circulatory and nervous systems. The neural communication of the gastrointestinal tract involves multiple levels, starting with the myenteric submucosal plexus and enteric glial cells, with the catecholaminergic neurons being closest to the gut's lumen [40]. The vagal nerve directly communicates with the myenteric plexus, connecting to prevertebral ganglia in the spinal cord and eventually to higher brain centres. ...
Parkinson’s disease (PD) is a neurodegenerative pathology, the origin of which is associated with the death of neuronal cells involved in the production of dopamine. The prevalence of PD has increased exponentially. The aim of this review was to describe the novel treatments for PD that are currently under investigation and study and the possible therapeutic targets. The pathophysiology of this disease is based on the formation of alpha-synuclein folds that generate Lewy bodies, which are cytotoxic and reduce dopamine levels. Most pharmacological treatments for PD target alpha-synuclein to reduce the symptoms. These include treatments aimed at reducing the accumulation of alpha-synuclein (epigallocatechin), reducing its clearance via immunotherapy, inhibiting LRRK2, and upregulating cerebrosidase (ambroxol). Parkinson’s disease continues to be a pathology of unknown origin that generates a significant social cost for the patients who suffer from it. Although there is still no definitive cure for this disease at present, there are numerous treatments available aimed at reducing the symptomatology of PD in addition to other therapeutic alternatives that are still under investigation. However, the therapeutic approach to this pathology should include a combination of pharmacological and non-pharmacological strategies to maximise outcomes and improve symptomatological control in these patients. It is therefore necessary to delve deeper into the pathophysiology of the disease in order to improve these treatments and therefore the quality of life of the patients.
... TORS is a high-pain procedure, 1,11,12 likely due to the disruption of mucosal neurovasculature. 13 Ultimately, we found that 28 doses of liquid oxycodone (equivalent to 28 pills) provided adequate analgesia for 68% of the TORS population. For the remaining 32% of patients, pain was adequately controlled with one RF. ...
Objectives
We previously reported that >50% of postoperative opioids prescribed at our institution went unused for common otolaryngologic procedures. Based on these findings, we instituted multimodal, evidence‐based guidelines for postoperative pain management. In the second part of our multiphasic study, we evaluated the effects of these guidelines on (1) quantity of unused opioids, (2) patient satisfaction, and (3) institutional perceptions toward the opioid epidemic and prescribing guidelines.
Methods
Standardized, procedure‐specific opioid prescription guidelines were created using prospective data from the first phase of our study and evidence from current literature. Again, we examined sialendoscopy, parotidectomy, parathyroidectomy/thyroidectomy, and transoral robotic surgery (TORS). Patients were surveyed at their first postoperative appointment. Groups from Phases I and II were compared. Attending physicians were surveyed before the start of the multiphasic project and after prescribing guidelines were implemented.
Results
Prescribing guidelines led to an average reduction in prescribed morphine milligram equivalents (MME) per patient by: 48% (sialendoscopy), 63% (parotidectomy), 60% (para/thyroidectomy), and 42% (TORS). Average used MME per patient for parotidectomy was significantly reduced (64%). The proportion of unused MME per patient and patient satisfaction scores did not significantly change after guidelines were implemented.
Conclusion
Implementation of opioid‐prescribing guidelines and the use of multimodal analgesia substantially reduced the amount of opioids prescribed across all procedures without impacting patient satisfaction.
Level of Evidence
2
