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.

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.

Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway.

Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.

Neural control of immune cell trafficking.

Leukocyte trafficking between blood and tissues is an essential function of the immune system that facilitates humoral and cellular immune responses. Within tissues, leukocytes perform surveillance and effector functions via cell motility and migration toward sites of tissue damage, infection, or inflammation. Neurotransmitters that are produced by the nervous system influence leukocyte trafficking around the body and the interstitial migration of immune cells in tissues. Neural regulation of leukocyte dynamics is influenced by circadian rhythms and altered by stress and disease. This review examines current knowledge of neuro-immune interactions that regulate leukocyte migration and consequences for protective immunity against infections and cancer.

B Cell Depletion and SARS-CoV-2 Vaccine Responses in Neuroimmunologic Patients.

OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.

Neuroinflammation Modulation via α7 Nicotinic Acetylcholine Receptor and Its Chaperone, RIC-3.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in or on various cell types and have diverse functions. In immune cells nAChRs regulate proliferation, differentiation and cytokine release. Specifically, activation of the α7 nAChR reduces inflammation as part of the cholinergic anti-inflammatory pathway. Here we review numerous effects of α7 nAChR activation on immune cell function and differentiation. Further, we also describe evidence implicating this receptor and its chaperone RIC-3 in diseases of the central nervous system and in neuroinflammation, focusing on multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Deregulated neuroinflammation due to dysfunction of α7 nAChR provides one explanation for involvement of this receptor and of RIC-3 in neurodegenerative diseases. In this review, we also provide evidence implicating α7 nAChRs and RIC-3 in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) involving neuroinflammation. Besides, we will describe the therapeutic implications of activating the cholinergic anti-inflammatory pathway for diseases involving neuroinflammation.

The Impact of IgA and the Microbiota on CNS Disease.

Although anatomically distant from the central nervous system (CNS), gut-derived signals can dynamically regulate both peripheral immune cells and CNS-resident glial cells to modulate disease. Recent discoveries of specific microbial taxa and microbial derived metabolites that modulate neuroinflammation and neurodegeneration have provided mechanistic insight into how the gut may modulate the CNS. Furthermore, the participation of the gut in regulation of peripheral and CNS immune activity introduces a potential therapeutic target. This review addresses emerging literature on how the microbiome can affect glia and circulating lymphocytes in preclinical models of human CNS disease. Critically, this review also discusses how the host may in turn influence the microbiome, and how this may impact CNS homeostasis and disease, potentially through the production of IgA.

Neuroimmune multi-hit perspective of coronaviral infection.

It is well accepted that environmental stressors experienced over a one's life, from microbial infections to chemical toxicants to even psychological stressors, ultimately shape central nervous system (CNS) functioning but can also contribute to its eventual breakdown. The severity, timing and type of such environmental "hits", woven together with genetic factors, likely determine what CNS outcomes become apparent. This focused review assesses the current COVID-19 pandemic through the lens of a multi-hit framework and disuses how the SARS-COV-2 virus (causative agent) might impact the brain and potentially interact with other environmental insults. What the long-term consequences of SAR2 COV-2 upon neuronal processes is yet unclear, but emerging evidence is suggesting the possibility of microglial or other inflammatory factors as potentially contributing to neurodegenerative illnesses. Finally, it is critical to consider the impact of the virus in the context of the substantial psychosocial stress that has been associated with the global pandemic. Indeed, the loneliness, fear to the future and loss of social support alone has exerted a massive impact upon individuals, especially the vulnerable very young and the elderly. The substantial upswing in depression, anxiety and eating disorders is evidence of this and in the years to come, this might be matched by a similar spike in dementia, as well as motor and cognitive neurodegenerative diseases.

Microbiota-Gut-Brain Axis and Epilepsy: A Review on Mechanisms and Potential Therapeutics.

The gut-brain axis refers to the bidirectional communication between the gut and brain, and regulates intestinal homeostasis and the central nervous system via neural networks and neuroendocrine, immune, and inflammatory pathways. The development of sequencing technology has evidenced the key regulatory role of the gut microbiota in several neurological disorders, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Epilepsy is a complex disease with multiple risk factors that affect more than 50 million people worldwide; nearly 30% of patients with epilepsy cannot be controlled with drugs. Interestingly, patients with inflammatory bowel disease are more susceptible to epilepsy, and a ketogenic diet is an effective treatment for patients with intractable epilepsy. Based on these clinical facts, the role of the microbiome and the gut-brain axis in epilepsy cannot be ignored. In this review, we discuss the relationship between the gut microbiota and epilepsy, summarize the possible pathogenic mechanisms of epilepsy from the perspective of the microbiota gut-brain axis, and discuss novel therapies targeting the gut microbiota. A better understanding of the role of the microbiota in the gut-brain axis, especially the intestinal one, would help investigate the mechanism, diagnosis, prognosis evaluation, and treatment of intractable epilepsy.

Molecular Mechanisms of Neuroimmune Crosstalk in the Pathogenesis of Stroke.

Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood-brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.

Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.

BACKGROUND: Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. METHODS: Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). RESULTS: Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). CONCLUSIONS: Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.

Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.

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.

Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.

Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1ß production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.

Efficient roles of miR-146a in cellular and molecular mechanisms of neuroinflammatory disorders: An effectual review in neuroimmunology.

Known as one of the most sophisticated systems of the human body, the nervous system consists of neural cells and controls all parts of the body. It is closely related to the immune system. The effects of inflammation and immune reactions have been observed in the pathogenesis of some neurological disorders. Defined as the gene expression regulators, miRNAs participate in cellular processes. miR-146a is a mediator in the neuroimmune system, leaving substantial effects on the homeostasis of immune and brain cells, neuronal identities acquisition, and immune responses regulation in the nervous system. Its positive efficiency has been proven in modulating inflammatory reactions, hemorrhagic complications, and pain. Moreover, the miR-146a targets play a key role in the pathogenesis of these illnesses. Based on the performance of its targets, miR-146a can have various effects on the disease progress. The abnormal expression/function of miR-146a has been reported in neuroinflammatory disorders. There is research evidence that this molecule qualifies as a desirable biomarker for some disorders and can even be a therapeutic target. This study aims to provide a meticulous review regarding the roles of miR-146a in the pathogenesis and progression of several neuroinflammatory disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, temporal lobe epilepsy, ischemic stroke, etc. The study also considers its eligibility for use as an ideal biomarker and therapeutic target in these diseases. The awareness of these mechanisms can facilitate the disease management/treatment, lead to patients' amelioration, improve the quality of life, and mitigate the risk of death.

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.

Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care.

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.