The nonclassical MHC class I Qa-1 expressed in layer 6 neurons regulates activity-dependent plasticity via microglial CD94/NKG2 in the cortex.

During developmental critical periods, circuits are sculpted by a process of activity-dependent competition. The molecular machinery involved in regulating the complex process of responding to different levels of activity is now beginning to be identified. Here, we show that the nonclassical major histocompatibility class I (MHCI) molecule Qa-1 is expressed in the healthy brain in layer 6 corticothalamic neurons. In the visual cortex, Qa-1 expression begins during the critical period for ocular dominance (OD) plasticity and is regulated by neuronal activity, suggesting a role in regulating activity-dependent competition. Indeed, in mice lacking Qa-1, OD plasticity is perturbed. Moreover, signaling through CD94/NKG2, a known cognate Qa-1 heterodimeric receptor in the immune system, is implicated: selectively targeting this interaction phenocopies the plasticity perturbation observed in Qa-1 knockouts. In the cortex, CD94/NKG2 is expressed by microglial cells, which undergo activity-dependent changes in their morphology in a Qa-1­dependent manner. Our study thus reveals a neuron­microglial interaction dependent upon a nonclassical MHCI molecule expressed in L6 neurons, which regulates plasticity in the visual cortex. These results also point to an unexpected function for the Qa-1/HLA-E (ligand) and CD94/NKG2 (receptor) interaction in the nervous system, in addition to that described in the immune system.

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.

A Heart Rate Step Function Response Method for the Evaluation of Pulse Wave Velocity as a Predictor of Major Adverse Cardio-Vascular Events.

Background and Objectives: Cardiovascular diseases are the main cause of death worldwide, and pulse wave velocity (PWV) is considered a predictor of major adverse cardiovascular events. The study intended to be helpful in finding methods for the preliminary assessment of PWV in primary care units. Materials and Methods: The study group consisted of 36 subjects (considered healthy by their own statement) from the medical field (medicine students and residents) aged between 20 and 30 years: 33.3% males and 66.7% females. Two types of measurements were carried out successively: (a) measurements with the arteriograph and (b) measurements on a treadmill effort testing system, where heart rate (HR) was measured over time as a response to step function physical effort (PE). Results: The study allowed for the highlighting of some limits which, if exceeded, can be associated with high PWV values: (i) if after a moderate PE and a resting time of at least 6 min, the HR is larger than 80 b/min; (ii) if the relaxation time in a PE test of moderate intensity is larger than 1 min; (iii) if the HR measured after the subject is raised from the supine to orthostatic position is larger than 100 b/min, and (iv) if the resting HR is larger than 80 b/min. Conclusions: Steady-state HR correlates with PWV and may be used for the preliminary assessment of PWV.

Pulse Wave Velocity, a Predictor of Major Adverse Cardiovascular Events, and Its Correlation with the General Stress Level of Health Care Workers during the COVID-19 Pandemic.

Background and Objectives: In the COVID-19 epidemiological context, the health care workers who were treating patients with COVID-19 were exposed daily to additional stress. Pulse wave velocity (PWV) is a predictive parameter for possible major adverse cardiovascular events. The present study aimed to evaluate the correlation between the general stress levels and PWVs of medical workers during the COVID-19 pandemic. Materials and Methods: The study group was heterogeneous in terms of the medical profession. PWV was measured using a TendioMed arteriograph. Assessment of stress level was performed using a general stress questionnaire with questions grouped on the areas that contribute to stress: lifestyle, environment, symptoms, job, relationships and personality. PWV measurements and stress assessment were performed both during the period with many patients with COVID-19 and during the period with few patients with COVID-19. Results: The stress levels and PWVs of subjects were higher in the period when they cared for patients with COVID-19 than in the period when they did not have patients with COVID-19. Conclusions: The study shows a positive correlation between the PWV of each subject and his/her stress score (the higher the stress score, the higher the PWV).

Learning and memory ... and the immune system.

The nervous system and the immune system are two main regulators of homeostasis in the body. Communication between them ensures normal functioning of the organism. Immune cells and molecules are required for sculpting the circuitry and determining the activity of the nervous system. Within the parenchyma of the central nervous system (CNS), microglia constantly monitor synapses and participate in their pruning during development and possibly also throughout life. Classical inflammatory cytokines, such as interleukin (IL)-1ß and tumor necrosis factor (TNF), are released during neuronal activity and play a crucial role in regulating the strength of synaptic transmission. Systemically, proper functioning of the immune system is critical for maintaining normal nervous system function. Disruption of the immune system functioning leads to impairments in cognition and in neurogenesis. In this review we provide examples of the communication between the nervous and the immune systems in the interest of normal CNS development and function.

Experimental autoimmune encephalomyelitis is associated with changes of the microbiota composition in the gastrointestinal tract.

The gut microbiome is known to be sensitive to changes in the immune system, especially during autoimmune diseases such as Multiple Sclerosis (MS). Our study examines the changes to the gut microbiome that occur during experimental autoimmune encephalomyelitis (EAE), an animal model for MS. We collected fecal samples at key stages of EAE progression and quantified microbial abundances with 16S V3-V4 amplicon sequencing. Our analysis of the data suggests that the abundance of commensal Lactobacillaceae decreases during EAE while other commensal populations belonging to the Clostridiaceae, Ruminococcaceae, and Peptostreptococcaceae families expand. Community analysis with microbial co-occurrence networks points to these three expanding taxa as potential mediators of gut microbiome dysbiosis. We also employed PICRUSt2 to impute MetaCyc Enzyme Consortium (EC) pathway abundances from the original microbial abundance data. From this analysis, we found that a number of imputed EC pathways responsible for the production of immunomodulatory compounds appear to be enriched in mice undergoing EAE. Our analysis and interpretation of results provides a detailed picture of the changes to the gut microbiome that are occurring throughout the course of EAE disease progression and helps to evaluate EAE as a viable model for gut dysbiosis in MS patients.

Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia.

Peripherally derived macrophages infiltrate the brain after bone marrow transplantation and during central nervous system (CNS) inflammation. It was initially suggested that these engrafting cells were newly derived microglia and that irradiation was essential for engraftment to occur. However, it remains unclear whether brain-engrafting macrophages (beMφs) acquire a unique phenotype in the brain, whether long-term engraftment may occur without irradiation, and whether brain function is affected by the engrafted cells. In this study, we demonstrate that chronic, partial microglia depletion is sufficient for beMφs to populate the niche and that the presence of beMφs does not alter behavior. Furthermore, beMφs maintain a unique functional and transcriptional identity as compared with microglia. Overall, this study establishes beMφs as a unique CNS cell type and demonstrates that therapeutic engraftment of beMφs may be possible with irradiation-free conditioning regimens.

Central Nervous System: (Immunological) Ivory Tower or Not?

The view of the nervous system being the victim of destructive inflammation during autoimmunity, degeneration, or injury has been rapidly changing. Recent studies are supporting the idea that the immune system provides support for the nervous system at various levels. Though cell patrolling through the nervous system parenchyma is limited compared with other tissues, immune cell presence within the central nervous system (CNS; microglia), as well as around it (in the meningeal spaces and choroid plexus) has been shown to be important for brain tissue maintenance and function. This review primarily explores recent findings concerning neuroimmune interactions and their mechanisms under homeostatic conditions.

Microbiota alteration is associated with the development of stress-induced despair behavior.

Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress.