Neuroendocrine-immunology has achieved substantial progress and growth over the last year. As the BrainImmune mission is to promote the advancement of this research field, it is becoming a tradition to recapitulate the latest developments in this relatively new interdisciplinary area that bridges neurosciences and immunology. Note that this is not a complete list, but rather a snapshot of our understanding how the field developed, outlining some major concepts and ideas published in 2016, as discussed here on BrainImmune. Also, the work and progress highlighted below, indicates that the vast interdisciplinary research area of neuroendocrine-immunology has a great potential fundamentally, clinically and pharmacologically, and important implications for common human immune/inflammatory diseases.
Anatomy & ImmunoPhysiology
Fig.1 wAPC in human lymph nodes (see text).
2016 brought the identification of a new morphological structure in lymphoid organs. More than 100 years since Tonkoff first reported in 1899 that nerves enter lymph nodes, Clemens Wülfing & Hauke S. Günther provided the first evidence for a parenchymal innervation of lymph nodes, besides the well-known neuronal inputs terminating at the lymphoid vasculature. They reported the presence of closely associated meshwork of neuronal fibers – a neural meshwork resembling glass fishing float that envelops antigen presenting cells (APC). The authors named these structures “wired” APC (wAPC) – emphasizing the ‘directed-informational contact’ to the wAPC.
As per this study, in lymph nodes, the APCs are abundantly innervated in the T-cell enriched area, the subsinoidal layer and the cortical extrafollicular zone, and the innervated cells appear to be mostly macrophages and dendritic cells. The authors suggest that this meshwork of neuronal fibers represents a form of topographically organized afferent sensory system in the brain-immune interactions.
Another 2016 Journal of Experimental Medicine study, by Kazuhiro Suzuki et al. from the Immunology Frontier Research Center, Osaka reveals a mechanism that drives the circadian rhythmicity in the immune system. In this process, the input from sympathetic nerves to β2-adrenorecepors (ARs) on lymphocytes is essential, and signaling exerted by catecholamines on β2-ARs generates circadian rhythms of lymphocyte egress from lymph nodes, controlling the lymphocyte recirculation in lymphoid organs. This study also implicates the noradrenergic input and the β2-ARs signaling in driving the nocturnal enhancement of adaptive immunity.
A Cell report by Mauricio Farez et al. indicates that melatonin may contribute to the seasonality of multiple sclerosis (MS) relapses. The authors suggest that melatonin, whose levels show seasonal variability, controls the balance between pathogenic T helper (Th)17 and regulatory T cells. They report that melatonin suppresses the generation of Th17 cells by acting via its membrane receptors in NFIL3-dependent fashion, and promotes Tr1 cell differentiation by activating ROR-alpha and Erk1/2 signaling which controls interleukin (IL)-10 expression. According to Georges Maestroni, who is an established expert in this field, this may represent one of the most important physiological effects of melatonin.
Neuroscience & Neuroimmunology
A 2016 Nature magazine study connects the meningeal immunity to social behavior, linking the regulatory effects of meningeal interferon (IFN)-γ to the activity of the brain cortex GABAergic neurons. Here, Anthony Filiano and colleagues, from the Center for Brain Immunology and Glia, University of Virginia, Charlottesville, Virginia, report that the intra-cerebrospinal injection of IFN-γ is able to increase the tonic GABAergic inhibitory current of layer I cortical neurons.
Thus, the brain cortical neurons are able to respond to IFN-γ signals derived from meningeal T cells and to elevate tonic GABAergic inhibition and, hence, prevent aberrant hyper-excitability in the prefrontal cortex. As per the authors of this study, an adaptive immune dysfunction, mediated by IFN-γ, can produce social dysfunction, suggesting a co-evolutionary link between social behavior and the IFN-γ anti-pathogen immune response. The study is relevant to diseases such as autism spectrum disorder, frontotemporal dementia and schizophrenia where serious social and immune dysfunction has been documented.
A 2016 Science report by Gloria Choi and colleagues from the Massachusetts Institute of Technology, Cambridge, MA, demonstrates that the highly pathogenic/pro-inflammatory cytokine IL-17a affects the normal brain development in a mouse model of autism, causing disorganized cortical cytoarchitecture and autism-like symptoms. As viral infection during pregnancy in humans may correlate with increased frequency of autism in the offspring, here, Choi et al. has modeled this in rodents using the maternal immune activation (MIA) protocol.
The authors found that Th17 cells and IL-17 are required in mothers for MIA-induced behavioral abnormalities in offspring. Thus, pregnant mothers, injected with poly(I:C), had a strong induction of serum IL-6 and IL-17 cytokine levels (of note, IL-6 is a key factor for Th17 cell differentiation). Also, the expression of the IL-17 receptor subunit A (IL-17Ra) was strongly augmented in the fetal brain upon induction of MIA. Of note, the maternal IL-17a induced abnormal cortical development in offspring related to patches of disorganized cortical cytoarchitecture.
A PLoS One study shows that the brain microglia – T cells interactions, and the release of IL-1β and IL-23 during this process results in activation of γδ T cells and the secretion of vast amounts of IL-17. These effects are related to neurotoxicity in vitro that required a direct cell-cell contact between T cells and neurons. The study implicates activated microglia in polarization of γδ T cells towards neurotoxic IL-17+ γδ T cells. According to the authors, their work suggests that, in clinical settings, the entry of γδ T cells into the brain may cause intracellular production of the highly pathogenic IL-17, via contact with microglia.
New research indicates that the TNF expression by both neurons and glial cells of the brain governs the development and maintenance of neuropathic pain. TNF mediates neuropathic pain through its activity on nerve terminals, inhibiting the release of norepinephrine (NE), and enhancing activity (supersensitization) of the presynaptic α2-adrenergic inhibitory autoreceptor, which is a primary regulator of NE release.
This research substantiates that α2-adrenergic autoinhibitory receptor supersensitization during persistent pain is associated with increases in TNF levels within neurons. Thus, a cross-talk occurs between α2-adrenergic receptors and TNF production that dictates changes in neuron activity during chronic pain.
A study in Endocrinology indicates that the adipose tissue macrophage (ATMs) production of tumor necrosis factor (TNF)-α is tonically suppressed by the activity of the sympathetic nervous system (SNS) and its β2-adrenoceptor signaling. This sustains at low levels of the production of this pro-inflammatory cytokine in lean mice.
Thus, in the fat tissue of lean animals, a longstanding suppression of the β-adrenoceptor function may keep the balance of anti-inflammatory versus inflammatory state towards anti-inflammation. This may also indicates that the sympathetic nerve-immune system interface and the anti-inflammatory SNS impact on macrophages might be dysfunctional in obese animals, and perhaps, in humans with obesity.
Immunology & Neuroendocrine Immunology
A 2016 Cell report by Ilana Gabanyi et al. provide evidence that in the gut 1) there is neuron-macrophage ‘‘structural coupling’’; 2) the sympathetic innervation is activated and norepinephrine (noradrenaline) signals to β2-adrenoreceptors on macrophages upon distal bacterial infection, and 3) in this process, during infection, β2-adrenoreceptors signaling mediates M2 macrophage polarization.
Of note, in the gut, lamina propria macrophages (LpMs) express a pro-inflammatory, M1 phenotype, while muscularis macrophages (MMs) display a tissue-protective, anti-inflammatory, M2 phenotype. The authors found that enteric neurons are surrounded by macrophages, that these neurons release norepinephrine (noradrenaline), the autonomic/sympathetic nervous system neurotransmitter involved in the stress response, and to ‘instruct’ macrophages to activate an the M2 anti-inflammatory response. Gut macrophages differentially expressed the β2-adrenergic receptors on their surface, and MMs expressed high levels of β2-ARs, while LpMs expressed lower levels. This finding suggests a mechanism by which sympathetic neurons signal the immune cells to restrict inflammation, even though they are not in direct contact with the pathogen.
A 2016 Journal of Immunology study indicates that in murine bone marrow–derived dendritic cells (DCs), norepinephrine, via stimulation of β2-adrenoceptors endorses a shift in the IL-12p70/IL-23 cytokine ratio. In the study, stimulation of DCs (or co-cultures of naive T cells with DCs) by norepinephrine or selective β2-adrenoceptor agonists induced an inhibition of IL-12p70 and IFN-γ secretion, but an increase in IL-17A production, without affecting the IL-23 production.
These results suggest that in lymphoid organs, the major sympathetic neurotransmitter norepinephrine may facilitate Th17 responses, shifting the IL-12p70/IL-23 ratio in favor of IL-23. This, according to Takenaka et al. may indicate how the activity of sympathetic nervous system, which is altered during acute or chronic stress, affects the onset or progression of inflammatory/autoimmune diseases.
A recent study published in Immunology is perhaps the first to demonstrate a correlation between glucocorticoid resistant IL-17- and IL-22-secreting T cells, and the number of active brain lesions in multiple sclerosis (MS).
As Afro-descendants, compared to Caucasians, expressed higher production of IL-17 and IL-22, related to a pronounced glucocorticoid resistance of their T cells, the authors of this study suggest that this may help explain why MS prognosis is worse among Afro-descendants patients. Moreover, the IL-17 and IL-22 glucocorticoid resistance may also contribute to worse prognosis in all MS patients, and importantly, may also reveal a biological marker at the early stage of MS.
A new report published in Oncotarget links β3-adrenoreceptors (ARs) to melanoma aggressiveness and progression. As per the study of Maura Calvani et al. from the University of Florence, β3-ARs are expressed on cancer cells, but also on stromal, inflammatory and vascular cells of the melanoma microenvironment. β3-ARs mediate the recruitment of fibroblasts, monocytes, bone marrow precursors and endothelial cells, whereas the contact with M2-polarized macrophages induced β3-ARs expression in cancer cells.
Importantly, β3-AR activation in melanoma accessory cells induce the release of pro-inflammatory cytokines such as IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, up-regulating tumor growth and melanoma aggressiveness. Moreover, ligand stimulation of β-ARs by the sympathetic neurotransmitter norepinephrine (noradrenaline) enhanced basal ERK1/2 activation, thus including norepinephrine within the large set of soluble factors that can enhance stromal reactivity and recruit bone marrow precursors to tumor site. This report suggests that β-adrenoreceptor (beta)-blockers may provide new therapeutic opportunities in melanoma and cancer.
In fact, recently Marisa Coelho et al. summarized the new research indicating that beta-adrenoceptors contribute to tumor development and that beta-blockers are potentially a novel class of antitumor agents. This is based on the increasing body of evidence suggesting that catecholamine-dependent signaling may represent a major link between chronic stress and tumor progression.
Stress & Stress-Immune Interactions
A recent Biological Psychiatry study by Masaaki Iwata et al. indicates that psychological stress is recognized, perceived or sensed by the brain’s immune system through the ATP/P2X7R–NLRP3 inflammasome cascade. The authors identified the pathways by which psychological stress increases IL-1β and the resulting neurogenic and anhedonic responses.
They found that stress promptly increased glutamate and extracellular ATP levels in the hippocampus. Thus, glutamate releases ATP as a gliotransmitter from astrocytes. Then, ATP activates P2X7R and releases IL-1β with subsequent induction of TNF-α via activation of the NLRP3 inflammasome. Importantly, the use of a P2X7R antagonist (which blocked the release of IL-1β and TNFα) also blocked behavioral deficits caused by chronic unpredictable stress.
A study in the Heart journal indicates that men with low stress resilience during youth are prone to approximately 40% increase in the risk of developing hypertension in later life, but the combination of low stress resilience and high body mass index (BMI) triples the hypertension risk.
Using 1,547,182 military conscripts from the Swedish Military Conscription Registry, the researchers found that men with low resilience to stress at the age of 18 had an increased risk to develop hypertension in adulthood. The study, although observational, suggests that the stress resilience-hypertension link may have an important long-term role in etiological pathways for hypertension, and that these pathways most likely are exaggerated in overweight individuals.
A study in Molecular Psychiatry indicates that chronic stress generates structural remodelling of the brain amygdala, and particularly the shrinkage of medial amygdala neurons in mice. T Lau et al. from the Laboratory of Neuroendocrinology, the Rockefeller University, NY report that chronically stressed mice exhibit structural modifications in neurons of the amygdala that can be partially prevented by treating the animals with the novel antidepressant candidate acetyl-L-carnitine (LAC). As per this study, in the basolateral amygdala stress was associated with an increase in dendritic length in pyramidal neurons, but the neuronal branches of the medial amygdala (mainly involved with the expression of emotions) appeared to shrink after 21 days of chronic stress.
The authors discuss that the stress-induced structural shrinkage in the medial amygdala, may represent a homeostatic adaptation to the increased glutamatergic overflow from the adjacent hippocampus, which directly projects to the medial amygdala. Thus, the medial amygdala is identified in this study as a novel target of structural and functional remodeling by chronic stress, and the new antidepressant candidate acetyl-L-carnitine.
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