Neuroimmune Crosstalk Research Articles

Sexually Dimorphic Immune and Neuroimmune Changes Following Peripheral Nerve Injury in Mice: Novel Insights for Gender Medicine.

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender in NeP onset is worldwide reported, and although the cause is generally attributed to sex hormones, the actual mechanisms and the players involved are still unclear. Glial and immune cells take part in NeP development, and orchestrate the neuroimmune and inflammatory response, releasing pro-inflammatory factors with chemoattractant properties that activate resident immune cells and recruit immune cells from circulation. The neuro-immune crosstalk is a key contributor to pain hypersensitivity following peripheral nervous system injury. Our previous works showed that in spite of the fact that female mice had an earlier analgesic response than males following nerve lesion, the recovery from NeP was never complete, suggesting that this difference could occur in the very early stages after injury. To further investigate gender differences in immune and neuroimmune responses to NeP, we studied the main immune cells and mediators elicited both in plasma and sciatic nerves by peripheral nerve lesion. After injury, we found a different pattern of distribution of immune cell populations showing either a higher infiltration of T cells in nerves from females or a higher infiltration of macrophages in nerves from males. Moreover, in comparison to male mice, the levels of cytokines and chemokines were differently up- and down-regulated in blood and nerve lysates from female mice. Our study provides some novel insights for the understanding of gender-associated differences in the generation and perseveration of NeP as well as for the isolation of specific neurodegenerative mechanisms underlying NeP. The identification of gender-associated inflammatory profiles in neuropathy is of key importance for the development of differential biomarkers and gender-specific personalized medicine.

Listening to the Whispers in Neuroimmune Crosstalk: A Comprehensive Workflow to Investigate Neurotrophin Receptor p75NTR Under Endogenous, Low Abundance Conditions.

Inflammatory conditions are critically influenced by neuroimmune crosstalk. Cytokines and neurotrophic factors shape the responses of both nervous and immune systems. Although much progress has been made, most findings to date are based on expression of recombinant (tagged) proteins. The examination of receptor interactions by immunoprecipitation (IP) at endogenous levels provides further insight into the more subtle regulations of immune responses. Here, we present a comprehensive workflow and an optimized IP protocol that provide step-by-step instructions to investigate neurotrophin receptor p75NTR at endogenous, low abundance levels: from lysate preparation and confirmation of receptor expression to antibody validation and successful detection of protein-protein interactions. We employ human melanoma cell line A375 to validate specific antibodies and IP conditions, and apply these methods to explore p75NTR interactions in human leukemic plasmacytoid dendritic cell line PMDC05 detecting 14-3-3ϵ:p75NTR interaction in this cell type. With p75NTR as an exemplary protein, our approach provides a strategy to detect specific interaction partners even under endogenous, low abundance expression conditions.

Analyses of peripheral blood dendritic cells and magnetic resonance spectroscopy support dysfunctional neuro-immune crosstalk in Tourette syndrome.

Evidence supports that neurodevelopmental diseases, such as Tourette syndrome (TS), may involve dysfunctional neural-immune crosstalk. This could lead to altered brain maturation and differences in immune and stress responses. Dendritic cells (DCs) play a major role in immunity as professional antigen-presenting cells; changes in their frequency have been observed in several autoimmune conditions. In 18 TS patients (15 on stable pharmacological treatment, three unmedicated) and 18 age-matched healthy volunteers (HVs), we explored circulating blood-derived DCs and their relationship with clinical variables and brain metabolites, measured via proton magnetic resonance spectroscopy (1H-MRS). DC subsets, including plasmacytoid and myeloid type 1 and 2 dendritic cells (MDC1, MDC2), were studied with flow cytometry. 1H-MRS was used to measure total choline, glutamate plus glutamine, total creatine (tCr), and total N-acetylaspartate and N-acetylaspartyl-glutamate levels in frontal white matter (FWM) and the putamen. We did not observe differences in absolute concentrations of DC subsets or brain inflammatory metabolites between patients and HVs. However, TS patients manifesting anxiety showed a significant increase in MDC1s compared to TS patients without anxiety (p=0.01). We also found a strong negative correlation between MDC1 frequency and tCr in the FWM of patients with TS (p=0.0015), but not of HVs. Elevated frequencies of the MDC1 subset in TS patients manifesting anxiety may reflect a proinflammatory status, potentially facilitating altered neuro-immune crosstalk. Furthermore, the strong inverse correlation between brain tCr levels and MDC1 subset frequency in TS patients suggests a potential association between proinflammatory status and metabolic changes in sensitive brain regions.

Cutaneous Neuroimmune Interactions in Peripheral Neuropathic Pain States.

Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain.

Cutaneous mechanisms of itch signaling

Itch is defined as an unpleasant sensation that stimulates the scratch reflex. While acute itch, such as from an insect bite, is protective and serves as a warning signal for potential tissue damage, chronic itch significantly impairs quality of life. This condition is still poorly understood and lacks universally effective treatments. Uncovering the cellular and molecular mechanisms of chronic itch is crucial for the development of anti-itch therapies. Skin is the largest sensory organ in which itch sensation is initiated. Currently, knowledge of itch signaling pathways in the skin has focused on (1) neuroimmune crosstalk in itch and inflammation in the skin; (2) skin-expressed ion channels that regulate itch signaling; and (3) skin-derived antimicrobial peptides that act as endogenous pruritogens.

Immunosensation: Neuroimmune Cross Talk in the Skin.

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology.

Neurological involvement of COVID-19: from neuroinvasion and neuroimmune crosstalk to long-term consequences.

As the coronavirus disease 2019 (COVID-19) pandemic continues to be a multidimensional threat to humanity, more evidence of neurological involvement associated with it has emerged. Neuroimmune interaction may prove to be important not only in the pathogenesis of neurological manifestations but also to prevent systemic hyperinflammation. In this review, we summarize reports of COVID-19 cases with neurological involvement, followed by discussion of possible routes of entry, immune responses against coronavirus infection in the central nervous system and mechanisms of nerve degeneration due to viral infection and immune responses. Possible mechanisms for neuroprotection and virus-associated neurological consequences are also discussed.

Changes in blood-spinal cord barrier permeability and neuroimmune interactions in the underlying mechanisms of chronic pain.

Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood-spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.

Inflammation neuroscience: neuro-immune crosstalk and interfaces.

Inflammation is a key process in antimicrobial defence and tissue repair, and failure to properly regulate inflammation can result in tissue damage and death. Neural circuits play important roles throughout the course of an inflammatory response, and the neurophysiological and molecular mechanisms are only partly understood. Here, we review key evidence for the neural regulation of inflammation and discuss emerging technologies to further map and harness this neurophysiology, a cornerstone in the rapidly evolving field of inflammation neuroscience.

TRPV1 in Pain and Itch.

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel that is intensively expressed in the peripheral nerve system and involved in a variety of physiological and pathophysiological processes in mammals. Its activity is of great significance in transmitting pain or itch signals from peripheral sensory neurons to the central nervous system. The alteration or hypersensitivityof TRPV1 channelis well evidenced under variouspathological conditions. Moreover, accumulative studies have revealed that TRPV1-expressing (TRPV1+) sensory neurons mediate the neuroimmune crosstalk by releasing neuropeptides to innervated tissues as well as immune cells. In the central projection, TRPV1+ terminals synapse with the secondary neurons for the transmissionof pain and itch signalling. The intense involvement of TRPV1 and TRPV1+ neurons in pain and itch makes it a potential pharmaceutical target. Over decades, the basis of TRPV1 channel structure, the nature of its activity, and its modulation in pathological processes have been broadly studied and well documented. Herein, we highlight the role of TRPV1 and its associated neurons in sensing pain and itch. The fundamental understandings of TRPV1-involved nociception, pruriception, neurogenic inflammation, and cell-specific modulation will help bring out more effective strategies of TRPV1 modulation in treating pain- and itch-related diseases.

Angiotensin receptors and neuropathic pain.

Growing evidence implicates the renin–angiotensin system (RAS) in multiple facets of neuropathic pain (NP). This narrative review focuses primarily on the major bioactive RAS peptide, Angiotensin II (Ang II), and its receptors, namely type 1 (AT1R) and type 2 (AT2R). Both receptors are involved in the development of NP and represent potential therapeutic targets. We first discuss the potential role of Ang II receptors in modulation of NP in the central nervous system. Ang II receptor expression is widespread in circuits associated with the perception and modulation of pain, but more studies are required to fully characterize receptor distribution, downstream signaling, and therapeutic potential of targeting the central nervous system RAS in NP. We then describe the peripheral neuronal and nonneuronal distribution of the RAS, and its contribution to NP. Other RAS modulators (such as Ang (1-7)) are briefly reviewed as well. AT1R antagonists are analgesic across different pain models, including NP. Several studies show neuronal protection and outgrowth downstream of AT2R activation, which may lead to the use of AT2R agonists in NP. However, blockade of AT2R results in analgesia. Furthermore, expression of the RAS in the immune system and a growing appreciation of neuroimmune crosstalk in NP add another layer of complexity and therapeutic potential of targeting this pathway. A growing number of human studies also hint at the analgesic potential of targeting Ang II signaling. Altogether, Ang II receptor signaling represents a promising, far-reaching, and novel strategy to treat NP.

Celiac Vagus Nerve Stimulation Recapitulates Angiotensin II-Induced Splenic Noradrenergic Activation, Driving Egress of CD8 Effector Cells

SummaryAngiotensin II (AngII) is a peptide hormone that affects the cardiovascular system, not only through typical effects on the vasculature, kidneys, and heart, but also through less understood roles mediated by the brain and the immune system. Here, we address the hard-wired neural connections within the autonomic nervous system that modulate splenic immunity. Chronic AngII infusion triggers burst firing of the vagus nerve celiac efferent, an effect correlated with noradrenergic activation in the spleen and T cell egress. Bioelectronic stimulation of the celiac vagus nerve, in the absence of other challenges and independently from afferent signals to the brain, evokes the noradrenergic splenic pathway to promote release of a growth factor mediating neuroimmune crosstalk, placental growth factor (PlGF), and egress of CD8 effector T cells. Our findings also indicate that the neuroimmune interface mediated by PlGF and necessary for transducing the neural signal into an effective immune response is dependent on α-adrenergic receptor signaling.

Neuroimmune crosstalk and evolving pharmacotherapies in neurodegenerative diseases.

Neurodegeneration is characterized by gradual onset and limited availability of specific biomarkers. Apart from various aetiologies such as infection, trauma, genetic mutation, the interaction between the immune system and CNS is widely associated with neuronal damage in neurodegenerative diseases. The immune system plays a distinct role in disease progression and cellular homeostasis. It induces cellular and humoral responses, and enables tissue repair, cellular healing and clearance of cellular detritus. Aberrant and chronic activation of the immune system can damage healthy neurons. The pro-inflammatory mediators secreted by chief innate immune components, the complement system, microglia and inflammasome can augment cytotoxicity. Furthermore, these inflammatory mediators accelerate microglial activation resulting in progressive neuronal loss. Various animal studies have been carried out to unravel the complex pathology and ascertain biomarkers for these harmful diseases, but have had limited success. The present review will provide a thorough understanding of microglial activation, complement system and inflammasome generation, which lead the healthy brain towards neurodegeneration. In addition to this, possible targets of immune components to confer a strategic treatment regime for the alleviation of neuronal damage are also summarized.

Hyperactivity of Innate Immunity Triggers Pain via TLR2-IL-33-Mediated Neuroimmune Crosstalk

The innate immune system responds to infections that give rise to pain. How the innate immune system interacts with the sensory nervous system and contributes to pain is poorly understood. Here we report that hyperactivity of innate immunity primes and initiates pain states via the TLR2-interleukin-33 (IL-33) axis. Toll-like receptors (TLRs) are upregulated in the complete Freund's adjuvant (CFA) pain model, and knockout of TLR2 abolishes CFA-induced pain. Selective activation of TLR2/6 triggers acute pain via upregulation of IL-33 in the hindpaw, dorsal root ganglia (DRG), and spinal cord in an NLRP3-dependent manner. The IL-33 increase further initiates priming of nociceptive neurons and pain states. Finally, blocking IL-33 receptors at the spinal level mediates analgesia during acute and chronic inflammatory pain, underscoring an important function of IL-33 in pain signaling. Collectively, our data reveal a critical role of the TLR2-IL-33 axis in innate immune activation for pain initiation and maintenance.

Elevated inflammatory proteins in cerebrospinal fluid from patients with painful knee osteoarthritis are associated with reduced symptom severity

Neuroinflammation and periphery-to-CNS neuroimmune cross-talk in patients with painful knee osteoarthritis (OA) are poorly understood. We utilized proximity extension assay to measure the level of 91 inflammatory proteins in CSF and serum from OA patients and controls. The patients had elevated levels of 48 proteins in CSF indicating neuroinflammation. Ten proteins were correlated between CSF and serum and potentially involved in periphery-to-CNS neuroimmune cross-talk. Seven CSF proteins, all with previously reported neuroprotective effects, were associated with lower pain intensity and milder knee-related symptoms. Our findings indicate that neuroinflammation in OA could be protective and associated with less severe symptoms.

Critical Neurotransmitters in the Neuroimmune Network.

Immune cells rely on cell-cell communication to specify and fine-tune their responses. They express an extensive network of cell communication modes, including a vast repertoire of cell surface and transmembrane receptors and ligands, membrane vesicles, junctions, ligand and voltage-gated ion channels, and transporters. During a crosstalk between the nervous system and the immune system these modes of cellular communication and the downstream signal transduction events are influenced by neurotransmitters present in the local tissue environments in an autocrine or paracrine fashion. Neurotransmitters thus influence innate and adaptive immune responses. In addition, immune cells send signals to the brain through cytokines, and are present in the brain to influence neural responses. Altered communication between the nervous and immune systems is emerging as a common feature in neurodegenerative and immunopathological diseases. Here, we present the mechanistic frameworks of immunostimulatory and immunosuppressive effects critical neurotransmitters — dopamine (3,4-dihydroxyphenethylamine), serotonin (5-hydroxytryptamine), substance P (trifluoroacetate salt powder), and L-glutamate — exert on lymphocytes and non-lymphoid immune cells. Furthermore, we discuss the possible roles neurotransmitter-driven neuroimmune networks play in the pathogenesis of neurodegenerative disorders, autoimmune diseases, cancer, and outline potential clinical implications of balancing neuroimmune crosstalk by therapeutic modulation.

Neural Control of Immunity in Hypertension: Council on Hypertension Mid Career Award for Research Excellence, 2019.

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these 2 evolutionarily highly conserved systems has been recognized for long time, the investigation into the pathophysiological mechanisms underlying their crosstalk has been tackled only in recent decades. Recent work of the past years elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. This review will focus on the neural mechanisms regulating the immune response and the role of this neuroimmune crosstalk in hypertension. In this context, the review highlights the components of the brain-spleen axis with a focus on the neuroimmune interface established in the spleen, where neural signals shape the immune response recruited to target organs of high blood pressure.

Spinal microglia-neuron interactions in chronic pain.

Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.

Neuro-Immunity Controls Obesity-Induced Pain.

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptor hypersensitivity may result from the systemic state of inflammation characteristic of obesity as well as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally released neuropeptides, sustain immunocytes’ function. Here, we posit that along with mechanical stress stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping such harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity.

Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel.

Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mechanisms in visceral hypersensitivity, working toward understanding how gut microbiota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.