In recent clinical practice, a biomarker of vagal neuroimmunomodulation (NIM), namely the ratio of vagally-mediated heart rate variability (vmHRV) and CRP, was proposed to index the functionality of the cholinergic anti-inflammatory pathway. This study aims to transfer and extend the previous findings to two general population-based samples to explore the hypothesis that NIM-ratio is associated with all-cause mortality. Two large population studies (MIDUS 2: N = 1255 and Whitehall II wave 5: N = 7870) with complete data from a total of N = 3860 participants (36.1% females; average age = 56.3 years; 11.1% deaths, last exit 18.1 years post inclusion) were available. NIM indices were calculated using the vagally-mediated HRV measure RMSSD divided by measures of CRP (NIMCRP) or IL-6 (NIMIL6). The NIM-ratios were quartiled and entered into age, ethnicity and body mass index adjusted Cox proportional hazards models. For NIMIL6 the lowest quartile was 45% more likely to die during the observed period (max. 18 years follow-up) compared to the highest quartile (HR = 0.55 CI 0.41-0.73; p < .0001). NIMCRP parallel these results. Here we show that an easily computable index of IL-6 inhibition is associated with all-cause mortality in two large general population samples. These results suggest that this index might be useful for risk stratification and warrant further examination.

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a pandemic started in Wuhan, China, in 2019. The rapid spread of the disease in the world, unprecedented mortality rate, and lack of definitive treatment for the disease have led to a global effort to develop effective vaccines as well as new therapeutic interventions. Immune cells activation with excessive inflammation is an important pathophysiological feature of COVID-19 that may impair the various organs functions. Accordingly, these could cause dysfunction in the brain with some symptoms such as respiratory failure, headache, impaired consciousness, olfactory and taste disorders, and severe neurological disorders such as encephalitis. It was found that there is a two-way communication between the immune system and the nervous system through classical neurotransmitters, hormones, and cytokines. Among neurotransmitters, serotonin plays important roles in the immune system and in regulating inflammatory responses by central and peripheral mechanisms. This article aimed to review the two-way relationship between the immune and the nervous systems by focusing on the serotonergic system and the emerging COVID-19 disease.

Heat stress has a relevant effect on animal health and productivity. Stress and environmental changes can contribute to disease development, such as avian necrotic enteritis (NE). The goal of this study was to analyze the effects of heat stress applied to broiler chickens in an experimental model of co-infection with Clostridium perfringens and Eimeria spp. Therefore, the current study was designed to analyze the effect of heat stress to broiler chickens in an experimental model of infection or co-infection with Clostridium perfringens and Eimeria spp. C. perfringens was given in the poultry feed and the Eimeria infection was induced by gavage with a live oocysts vaccine dose 30 times higher than the manufacturer recommendation. We observed a reduction in the secretory IgA concentration in the jejunum and ileum in heat-stressed chickens compared to non-stressed chickens. Decreased maximum scores of intestinal necrosis, crypt abscesses and transmural lesions were observed in the heat-stressed chickens co-infected and infected with Eimeria compared to the respective unstressed groups. Heat stress caused an increase the intestinal lesion scores in chickens infected with C. perfringens only. The crypt depth was greater in chickens from the heat-stressed groups compared to the non-stressed groups. We also demonstrated that HS decreased infection and/or Eimeria development in the intestinal epithelium, reducing the harmful potential of C. perfringens.

Melatonin is well known for its circadian production by the pineal gland, and there is a growing body of data showing that it is also produced by many other cells and organs, including immune cells. The chronobiotic role of pineal melatonin, as well as its protective effects in vitro and in vivo, have been extensively explored. However, the interaction between the chronobiotic and defence functions of endogenous melatonin has been little investigated. This review details the current knowledge regarding the coordinated shift in melatonin synthesis from the pineal gland (circadian and monitoring roles) to the regulation of acute immune responses via immune cell production and autocrine effects, producing systemic interactions termed the immune-pineal axis. An acute inflammatory response drives the transcription factor, NFκB, to switch melatonin synthesis from pinealocytes to macrophages/microglia and, upon acute inflammatory resolution, back to pinealocytes. The potential pathophysiological relevance of immune-pineal axis dysregulation is highlighted, with both research and clinical implications, across several medical conditions, including host/parasite interaction, neurodegenerative diseases and cancer. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Chronically stressed individuals are reported to overconsume tasty, palatable foods like sucrose to blunt the psychological and physiological impacts of stress. Negative consequences of high-sugar intake on feeding behavior include increased metabolic disease burdens like obesity. However, the neural basis underlying long-term high-sugar intake-induced overeating during stress is not fully understood. To investigate this question, we used the two-bottle sucrose choice paradigm in mice exposed to chronic unpredictable mild stressors (CUMS) that mimic those of daily life stressors. After 21 days of CUMS paralleled by consecutive sucrose drinking, we explored anxiety-like behavior using the elevated plus maze and open field tests. The normal water-drinking stressed mice displayed more anxiety than the sucrose-drinking stressed mice. Although sucrose-drinking displayed anxiolytic effects, the sucrose-drinking mice exhibited binge eating (chow) and a compulsive eating phenotype. The sucrose-drinking mice also showed a significant body-weight gain compared to the water-drinking control mice during stress. We further found that c-Fos expression was significantly increased in the ventral part of the lateral septum (vLS) of the sucrose-treated stressed mice after compulsive eating. Pharmacogenetic activation of the vLS glutamate decarboxylase 2(GAD2) neurons maintained plain chow intake but induced a compulsive eating phenotype in the naïve GAD2-Cre mice when mice feeding was challenged by flash stimulus, mimicking the negative consequences of excessive sucrose drinking during chronic stress. Further, pharmacogenetic activation of the vLSGAD2 neurons aggravated anxiety of the stressed GAD2-Cre mice but did not alter the basal anxiety level of the naïve ones. These findings indicate the GABAergic neurons within the vLS may be a potential intervention target for anxiety comorbid eating disorders during stress.

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease that worsens with age. Here, we examined the influence of age on passive experimental autoimmune encephalomyelitis (P-EAE), a model to study MS, using young and mature adult 2D2 transgenic donor mice to induce pathology in WT C57BL6/J mice.

The aim of this work was to improve the knowledge of the role of histamine in breast cancer by assessing the therapeutic efficacy of histamine and histamine H4 receptor (H4R) ligands in a triple-negative breast cancer (TNBC) model developed in immunocompetent hosts. By using publicly available genomic data, we further investigated whether histidine decarboxylase (HDC) could be a potential biomarker.

Although the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer.

No abstract available

Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries.

Among chronically ill populations, affective disorders remain underdiagnosed and undertreated. A high degree of comorbidity exists between diabetes and affective disorders, particularly depression and anxiety. The mechanisms underlying stress-induced affective dysregulation are likely distinct from those induced by diabetes. A direct comparison between stress- and hyperglycemia-induced affective dysregulation could provide insight into distinct mechanistic targets for depression/anxiety associated with these different conditions.

Inflammatory pain is a significant global clinical challenge that involves both unpleasant sensory and emotional experiences. The treatment of pain is imminent, and we are committed to seeking new analgesics for pain relief. Transcrocetin meglumine salt (TCMS), a saffron metabolite derived from the crocin apocarotenoids, has exhibited the ability to cross the blood-brain barrier and exert neuroprotective effects. In this study, we aimed to investigate whether TCMS could ameliorate complete Freund's adjuvant (CFA)-induced inflammatory pain in mice and elucidate its underlying mechanisms.

Inflammation is clearly associated with Alzheimer disease (AD). Knockout of Nlrp3, a gene encoding an inflammasome sensor, has been shown to ameliorate AD pathology in a mouse model. Because AIM2 is the most dominant inflammasome sensor expressed in mouse brains, here we investigate whether Aim2 deletion also influences the phenotype of a 5XFAD AD mouse model.

Calcitriol and hydroxyderivatives of lumisterol and tachisterol are secosteroid hormones with immunomodulatory and anti-inflammatory properties. Since the beginning of the COVID-19 pandemic, several studies have correlated deficient serum concentrations of vitamin D3 (calcifediol) with increased severity of the course of SARS-CoV-2 infection. Among systemic complications, subjective (anosmia, ageusia, depression, dizziness) and objective (ischemic stroke, meningoencephalitis, myelitis, seizures, Guillain-Barré syndrome) neurological symptoms have been reported in up to 80% of severe COVID-19 patients. In this narrative review, we will resume the pathophysiology of SARS-CoV-2 infection and the mechanisms of acute and chronic neurological damage. SARS-CoV-2 can disrupt the integrity of the endothelial cells of the blood-brain barrier (BBB) to enter the nervous central system. Invasion of pro-inflammatory cytokines and polarization of astrocytes and microglia cells always in a pro-inflammatory sense together with the pro-coagulative phenotype of cerebral endothelial cells in response to both SARS-CoV-2 and immune cells invasion (immunothrombosis) are the major drivers of neurodamage. Calcitriol and hydroxyderivatives of lumisterol and tachisterol could play an adjuvant role in neuroprotection through mitigation of neuroinflammation and protection of endothelial integrity of the BBB. Dedicated studies on this topic are currently lacking and are desirable to confirm the link between vitamin D3 and neuroprotection in COVID-19 patients.

Rheumatoid arthritis (RA) can be comorbid with psychiatric symptoms. Brain abnormalities in RA patients and in arthritis models have been reported. However, it remains unclear when these abnormalities occur and where they are distributed. In this study, we analyzed spatiotemporal changes in gene expression in the brains of mice with collagen-induced arthritis (CIA).

The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-γ, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-γ, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-γ producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-γ producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process.

Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy) methyl) piperidine- 1-carboxylate (JZL184), is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p.)) of JZL184, in a murine model of lipopolysaccharide (LPS) -induced acute lung injury (ALI) 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL) and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone) blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in both communication and social interaction, besides repetitive or stereotyped behavior. Although the etiology is unknown, environmental factors such as valproic acid (VPA) increase the risk of ASD onset. Resveratrol (RSV), a neuroprotective molecule, has been shown to counteract the effects of intrauterine exposure to VPA. We aimed to evaluate histological parameters related to hippocampal morphology and to the distribution of parvalbumin- (PV), calbindin- (CB), and somatostatin-positive (SOM) interneurons sub-populations, in addition to evaluate the total/phosphorylation levels of PTEN, AKT, GSK3β and total CK2 in the animal model of autism induced by VPA, as well as addressing the potential protective effect of RSV. On postnatal day 120, histological analysis showed a loss in total neurons in the dentate gyrus (DG) and decreased CB+ neurons in DG and CA1 in VPA animals, both prevented by RSV. In addition, PV+ neurons were diminished in CA1, CA2, and CA3, and SOM+ were interestingly increased in DG (prevented by RSV) and decreased in CA1 and CA2. A hippocampal lesion similar to sclerosis was also observed in the samples from the VPA group. Besides that, VPA reduced AKT and PTEN immunocontent, and VPA increased CK2 immunocontent. Thus, this work demonstrated long-term effects of prenatal exposure to ASD in different sub-populations of interneurons, structural damage of hippocampus, and also alteration in proteins associated with pivotal cell signaling pathways, highlighting the role of RSV as a tool for understanding the pathophysiology of ASD.

Our group is interested in the cytotoxic mechanism during autoimmune neuroinflammation. Unexpectedly, we come across a case that presents a massive enhancement of cytotoxic behavior in lymphocytes, either in peripheral blood and cerebrospinal fluid. Interestingly, this specific patient was refractory to Methylprednisolone treatment. Hypothetically, the cytotoxic activity could represent a novel and complementary effector mechanism to NMOSD pathogenesis. Nevertheless, further investigation is needed to evaluate the extension and the clinical relevance of our finds.

Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic signaling system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a non-selective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20 mg/kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment did not affect VPA-induced upregulation of P2X4 and P2Y2 receptor expression in the hippocampus, and P2X4 receptor expression in the medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic signaling modulation in behavioral, molecular, and immunological aberrations described in VPA model, and indicate that the purinergic signaling system might be a potential target for pharmacotherapy in preclinical studies of ASD.