Sensory neurons: An integrated component of innate immunity.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.

Neuroimmune Interactions in Peripheral Organs.

Interactions between the nervous and immune systems were recognized long ago, but recent studies show that this crosstalk occurs more frequently than was previously appreciated. Moreover, technological advances have enabled the identification of the molecular mediators and receptors that enable the interaction between these two complex systems and provide new insights on the role of neuroimmune crosstalk in organismal physiology. Most neuroimmune interactions occur at discrete anatomical locations in which neurons and immune cells colocalize. Here, we describe the interactions of the different branches of the peripheral nervous system with immune cells in various organs, including the skin, intestine, lung, and adipose tissue. We highlight how neuroimmune crosstalk orchestrates physiological processes such as host defense, tissue repair, metabolism, and thermogenesis. Unraveling these intricate relationships is invaluable to explore the therapeutic potential of neuroimmune interactions.

The neuroimmune response during stress: A physiological perspective.

Stress is an essential adaptive response that enables the organism to cope with challenges and restore homeostasis. Different stressors require distinctive corrective responses in which immune cells play a critical role. Hence, effects of stress on immunity may vary accordingly. Indeed, epidemiologically, stress can induce either inflammation or immune suppression in an organism. However, in the absence of a conceptual framework, these effects appear chaotic, leading to confusion. Here, we examine how stressor diversity is imbedded in the neuroimmune axis. Stressors differ in the brain patterns they induce, diversifying the neuronal and endocrine mediators dispatched to the periphery and generating a wide range of potential immune effects. Uncovering this complexity and diversity of the immune response to different stressors will allow us to understand the involvement of stress in pathological conditions, identify ways to modulate it, and even harness the therapeutic potential embedded in an adaptive response to stress.

A body-brain circuit that regulates body inflammatory responses.

The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here we show that a peripheral immune insult strongly activates the body-brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

Brain borders at the central stage of neuroimmunology.

The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.

Navigating the blurred path of mixed neuroimmune signaling.

Evolution has created complex mechanisms to sense environmental danger and protect tissues, with the nervous and immune systems playing pivotal roles. These systems work together, coordinating local and systemic reflexes to restore homeostasis in response to tissue injury and infection. By sharing receptors and ligands, they influence the pathogenesis of various diseases. Recently, a less-explored aspect of neuroimmune communication has emerged: the release of neuropeptides from immune cells and cytokines/chemokines from sensory neurons. This article reviews evidence of this unique neuroimmune interplay and its impact on the development of allergy, inflammation, itch, and pain. We highlight the effects of this neuroimmune signaling on vital processes such as host defense, tissue repair, and inflammation resolution, providing avenues for exploration of the underlying mechanisms and therapeutic potential of this signaling.

Neuroimmunophysiology of the gastrointestinal tract.

Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.

The contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders the post-traumatic brain vulnerable to poor outcomes, and susceptible to neurological disease, is incomplete. It is well established that dysregulated and sustained immune responses elicit negative consequences after TBI; however, our understanding of the neuroimmune interface that facilitates crosstalk between central and peripheral immune reservoirs is in its infancy. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in both healthy and disease settings. It has been previously shown that disruption of this system exacerbates neuroinflammation in age-related neurodegenerative disorders such as Alzheimer's disease; however, we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. In this manuscript, we will offer a detailed overview of the holistic nature of neuroinflammatory responses in TBI, including hallmark features observed across clinical and animal models. We will highlight the structure and function of the meningeal lymphatic system, including its role in immuno-surveillance and immune responses within the meninges and the brain. We will provide a comprehensive update on our current knowledge of meningeal-derived responses across the spectrum of TBI, and identify new avenues for neuroimmune modulation within the neurotrauma field.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries.

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aß) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aß pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2-4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aß pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1ß, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Neuroimmunology of Cardiovascular Disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a leading cause of death and chronic disability worldwide. Yet, despite extensive intervention strategies the number of persons affected by CVD continues to rise. Thus, there is great interest in unveiling novel mechanisms that may lead to new treatments. Considering this dilemma, recent focus has turned to the neuroimmune mechanisms involved in CVD pathology leading to a deeper understanding of the brain's involvement in disease pathology. This review provides an overview of new and salient findings regarding the neuroimmune mechanisms that contribute to CVD. RECENT FINDINGS: The brain contains neuroimmune niches comprised of glia in the parenchyma and immune cells at the brain's borders, and there is strong evidence that these neuroimmune niches are important in both health and disease. Mechanistic studies suggest that the activation of glia and immune cells in these niches modulates CVD progression in hypertension and heart failure and contributes to the inevitable end-organ damage to the brain. This review provides evidence supporting the role of neuroimmune niches in CVD progression. However, additional research is needed to understand the effects of prolonged neuroimmune activation on brain function.

Behaviorally Conditioned Immune Responses: "To Learn New Things, Read Old Books and Papers".

BACKGROUND: More than a century ago, experimental work and clinical observations revealed the functional communication between the brain and the peripheral immune system. This is documented on the one hand by studies first demonstrating the effects of catecholamines on the circulation of leukocytes in experimental animals and humans, and on the other hand via the work of Russian physiologist Ivan Petrovic Pavlov and his coworkers, reporting observations that associative learning can modify peripheral immune functions. This work later fell into oblivion since little was known about the endocrine and immune system's function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. SUMMARY: In this article, we embark on a fascinating exploration of the historical trajectory of behaviorally conditioned immune responses. KEY MESSAGE: We will pay homage to the visionary scientists who laid the groundwork for this field of research, tracing its evolution from early theories of how associative learning can affect immunity to the modern-day insights that behavioral conditioning of pharmacological responses can be exploited to improve the efficacy of medical interventions for patients.

Quick Guide to Evolutionary Medicine in Neuroimmunomodulation: Why "Evolved for the Benefit of the Species" Is Not a Valid Argument.

BACKGROUND: Evolutionary medicine builds on evolutionary biology and explains why natural selection has left us vulnerable to disease. Unfortunately, several misunderstandings exist in the medical literature about the levels and mechanisms of evolution. Reasons for these problems start from the lack of teaching evolutionary biology in medical schools. A common mistake is to assume that "traits must benefit the species, as otherwise the species would have gone extinct in the past" confusing evolutionary history (phylogeny) with evolutionary function (fitness). SUMMARY: Here we summarise some basic aspects of evolutionary medicine by pointing out: (1) Evolution has no aim. (2) For adaptive evolution to occur, a trait does not have to be beneficial to its carrier throughout its entire life. (3) Not every single individual carrying an adaptive trait needs to have higher than average fitness. (4) Traits do not evolve for the benefit of the species. Using examples from the field of neuroimmunomodulation like sickness behaviour (nervous system), testosterone (hormones), and cytokines (immunity), we show how misconceptions arise from not differentiating between the explanatory categories of phylogeny (evolutionary history) and evolutionary function (fitness). KEY MESSAGES: Evolution has no aim but is an automatism that does not function for the benefit of the species. In evolution, successful individuals are those that maximise the transmission of their genes, and health and survival are just strategies to have the opportunity to do so. Thus, a trait enabling survival of the individual until reproductive age will spread even if at later age the same trait leads to disease and death. Natural and sexual selection do not select for traits that benefit the health or happiness of the individual, but for traits that increase inclusive fitness even if this increases human suffering. In contrast, our humane aim is to increase individual well-being. Evolutionary medicine can help us achieve this aim against evolutionary constraints.

Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier.

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain.

It was recently suggested that supplying the brain with new neurons could counteract Alzheimer's disease (AD). This provocative idea requires further testing in experimental models in which the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in AD and could help to understand the mechanisms to be harnessed for developing new neurons in diseased mammalian brains. Here, by performing single-cell transcriptomics, we found that amyloid toxicity-induced interleukin-4 (IL4) promotes NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of serotonin. NSC proliferation was suppressed by serotonin via down-regulation of brain-derived neurotrophic factor (BDNF)-expression in serotonin-responsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via nerve growth factor receptor A (NGFRA)/ nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFkB) signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after AD conditions in zebrafish.

The Neuroimmunology of Chronic Pain: From Rodents to Humans.

Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain.

The complement cascade is a key component of the innate immune system that is rapidly recruited through a cascade of enzymatic reactions to enable the recognition and clearance of pathogens and promote tissue repair. Despite its well-understood role in immunology, recent studies have highlighted new and unexpected roles of the complement cascade in neuroimmune interaction and in the regulation of neuronal processes during development, aging, and in disease states. Complement signaling is particularly important in directing neuronal responses to tissue injury, neurotrauma, and nerve lesions. Under physiological conditions, complement-dependent changes in neuronal excitability, synaptic strength, and neurite remodeling promote nerve regeneration, tissue repair, and healing. However, in a variety of pathologies, dysregulation of the complement cascade leads to chronic inflammation, persistent pain, and neural dysfunction. This review describes recent advances in our understanding of the multifaceted cross-communication that takes place between the complement system and neurons. In particular, we focus on the molecular and cellular mechanisms through which complement signaling regulates neuronal excitability and synaptic plasticity in the nociceptive pathways involved in pain processing in both health and disease. Finally, we discuss the future of this rapidly growing field and what we believe to be the significant knowledge gaps that need to be addressed.

Neural control of the spleen as an effector of immune responses to inflammation: mechanisms and treatments.

Immune system responses are a vital defense mechanism against pathogens. Inflammatory mediators finely regulate complex inflammatory responses from initiation to resolution. However, in certain conditions, the inflammation is initiated and amplified, but not resolved. Understanding the biological mechanisms underlying the regulation of the immune response is critical for developing therapeutic alternatives, including pharmaceuticals and bioelectronic tools. The spleen is an important immune effector organ since it orchestrates innate and adaptive immune responses such as pathogen clearance, cytokine production, and differentiation of cells, therefore playing a modulatory role that balances pro- and anti-inflammatory responses. However, modulation of splenic immune activity is a largely unexplored potential therapeutic tool that could be used for the treatment of inflammatory and life-threatening conditions. This review discusses some of the mechanisms controlling neuroimmune communication and the brain-spleen axis.

Restoring neuro-immune circuitry after brain and spinal cord injuries.

Neuro-immune interactions are essential for our body's defense and homeostasis. Anatomical and physiological analyses have shown that the nervous system comprises multiple pathways that regulate the dynamics and functions of immune cells, which are mainly mediated by the autonomic nervous system and adrenal signals. These are disturbed when the neurons and circuits are damaged by diseases of the central nervous system (CNS). Injuries caused by stroke or trauma often cause immune dysfunction by abrogation of the immune-regulating neural pathways, which leads to an increased risk of infections. Here, I review the structures and functions of the neural pathways connecting the brain and the immune system, and the neurogenic mechanisms of immune dysfunction that emerge after CNS injuries. Recent technological advances in manipulating specific neural circuits have added mechanistic aspects of neuro-immune interactions and their dysfunctions. Understanding the neural bases of immune control and their pathological processes will deepen our knowledge of homeostasis and lead to the development of strategies to cure immune deficiencies observed in various CNS disorders.

A 20-Year Journey from Axonal Injury to Neurodegenerative Diseases and the Prospect of Immunotherapy for Combating Alzheimer's Disease.

The understanding of the dialogue between the brain and the immune system has undergone dramatic changes over the last two decades, with immense impact on the perception of neurodegenerative diseases, mental dysfunction, and many other brain pathologic conditions. Accumulated results have suggested that optimal function of the brain is dependent on support from the immune system, provided that this immune response is tightly controlled. Moreover, in contrast to the previous prevailing dogma, it is now widely accepted that circulating immune cells are needed for coping with brain pathologies and that their optimal effect is dependent on their type, location, and activity. In this perspective, we describe our own scientific journey, reviewing the milestones in attaining this understanding of the brain-immune axis integrated with numerous related studies by others. We then explain their significance in demonstrating the possibility of harnessing the immune system in a well-controlled manner for the treatment of neurodegenerative diseases.