Brain, Behavior, and Immunity最新文献

Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.

Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In Pdgfrα^CreERT:Tnfrsf1b^fl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, Pdgfrα^CreERT:Tnfrsf1b^fl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated “foamy” phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) mediated by CD4⁺ T helper (Th) cells, and characterized by immune cell infiltration, demyelination and neurodegeneration, with no definitive cure available. Thus, it is pivotal and imperative to acquire more profound comprehension of the underlying mechanisms implicated in MS. Dysregulated immune responses are widely believed to play a primary role in the pathogenesis of MS. Recently, a plethora of studies have demonstrated the involvement of T follicular helper (Tfh) cells and tertiary lymphoid-like structures (TLSs) in the pathogenesis and progression of MS. Cathepsin C (CatC) is a cysteine exopeptidase which is crucial for the activation of immune-cell-associated serine proteinases in many inflammatory diseases in peripheral system, such as rheumatoid arthritis and septicemia. We have previously demonstrated that CatC is involved in neuroinflammation and exacerbates demyelination in both cuprizone-induced and experimental autoimmune encephalomyelitis (EAE) mouse models. However, the underlying immunopathological mechanism remains elusive. In the present study, we established a recombinant myelin oligodendrocyte glycoprotein 35–55 peptide-induced EAE model using conditional CatC overexpression mice to investigate the effects of CatC on the alteration of CD4⁺ Th subsets, including Th1, Th2, Th17, Tfh and T regulatory cells. Our findings demonstrated that CatC particularly enhanced the population of Tfh cell in the brain, resulting in the earlier onset and more severe chronic syndrome of EAE. Furthermore, CatC promoted the formation of TLSs in the brain, leading to persistent neuroinflammation and exacerbating the severity of EAE in the chronic phase. Conversely, treatment with AZD7986, a specific inhibitor of CatC, effectively attenuated the syndrome of EAE and its effects caused by CatC both in vivo and in vitro. These findings provide a novel insight into the critical role of CatC in innate and adaptive immunity in EAE, and specific inhibitor of CatC, AZD7986, may contribute to potential therapeutic strategies for MS.

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, with a highly diverse genetic hereditary component, including altered neuronal circuits, that has an impact on communication skills and behaviours of the affected individuals. Beside the recognised role of neuronal alterations, perturbations of microglia and the associated neuroinflammatory processes have emerged as credible contributors to aetiology and physiopathology of ASD. Mutations in NRXN1, a member of the neurexin family of cell-surface receptors that bind neuroligin, have been associated to ASD. NRXN1 is known to be expressed by neurons where it facilitates synaptic contacts, but it has also been identified in glial cells including microglia. Asserting the impact of ASD-related genes on neuronal versus microglia functions has been challenging. Here, we present an ASD subject-derived induced pluripotent stem cells (iPSC)-based in vitro system to characterise the effects of the ASD-associated NRXN1 gene deletion on neurons and microglia, as well as on the ability of microglia to support neuronal circuit formation and function. Using this approach, we demonstrated that NRXN1 deletion, impacting on the expression of the alpha isoform (NRXN1α), in microglia leads to microglial alterations and release of IL6, a pro-inflammatory interleukin associated with ASD. Moreover, microglia bearing the NRXN1α-deletion, lost the ability to support the formation of functional neuronal networks. The use of recombinant IL6 protein on control microglia-neuron co-cultures or neutralizing antibody to IL6 on their NRXN1α-deficient counterparts, supported a direct contribution of IL6 to the observed neuronal phenotype. Altogether, our data suggest that, in addition to neurons, microglia are also negatively affected by NRXN1α-deletion, and this significantly contributes to the observed neuronal circuit aberrations.

Traumatic brain injury (TBI) is a disabling neurotraumatic condition and the leading cause of injury-related deaths and disability in the United States. Attenuation of neuroinflammation early after TBI is considered an important treatment target; however, while these inflammatory responses can induce secondary brain injury, they are also involved in the repair of the nervous system. Pioglitazone, which activates peroxisome proliferator-activated receptor gamma, has been shown to decrease inflammation acutely after TBI, but the long-term consequences of its use remain unknown. For this reason, the impacts of treatment with pioglitazone during the acute/subacute phase (30 min after injury and each subsequent 24 h for 5 days) after TBI were interrogated during the chronic phase (30- and 274-days post-injury (DPI)) in mice using the controlled cortical impact model of experimental TBI. Acute/subacute pioglitazone treatment after TBI results in long-term deleterious consequences, including disruption of tau homeostasis, chronic glial cell activation, neuronal pathology, and worsened injury severity particularly at 274 DPI, with male mice being more susceptible than female mice. Further, male pioglitazone-treated TBI mice exhibited increased dominant and offensive-like behavior while having a decreased non-social exploring behavior at 274 DPI. After TBI, both sexes exhibited glial activation at 30 DPI when treated with pioglitazone; however, while injury severity was increased in females it was not impacted in male mice. This work reveals that although pioglitazone has been shown to lead to attenuated TBI outcomes acutely, sex-based differences, timing and long-term consequences of treatment with glitazones must be considered and further studied prior to their clinical use for TBI therapy.

Background

Individuals with Schizophrenia Spectrum Disorders (SSD) often suffer from obesity and do limited Physical Activity (PA). PA has many beneficial effects on a variety of somatic and mental variables and it should be strengthened among people with mental disorders. The relationship between Body Mass Index (BMI), Waist Circumference (WC), and PA in this population is poorly understood, with a lack of precise PA assessment. This study investigates the association between BMI, WC, weight, and PA in individuals with SSD and controls using accelerometers.

Methods

One hundred twenty-six patients with SSD (residents and outpatients) and 110 sex- and age-matched controls were enrolled. Clinical, sociodemographic, and quality-of-life data were collected. PA was measured with a tri-axial ActiGraph GT9X and quantified by Vector Magnitude (VM). Relationships between PA and BMI, WC, and weight changes were analysed using linear regression models.

Results

Patients were more likely to be unmarried, unemployed, and less educated compared to controls (p < 0.001). Residents had more medical comorbidities (p = 0.001), while outpatients had higher BMI, weight, and WC (p < 0.001). Residents reported more severe psychopathology, lower functioning, and greater use of psychopharmacological medications (p < 0.001). Higher PA levels were not significantly associated with lower BMI, WC, or weight. Although not statistically significant, increased PA showed a trend towards lower obesity risk.

Conclusions

Sociodemographic, medical, and clinical characteristics of individuals with SSD define vulnerability factors that can inform tailored interventions to improve PA.

Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2_LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2_LD in patients with bipolar depression. Patients received a placebo or IL-2_LD (1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2_LD assessed by fold increase in Treg percentage of CD4 + cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, number NCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2_LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2_LD expanding 1.17 [95 % CI 1.01–1.34] vs 1.01 [95 % CI 0.90–1.12] (p = 0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2_LD treated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2_LD as an adjunct treatment of major mood disorders.

Much evidence on heightened inflammation and social behavior focuses on social withdrawal. Building on recent theory (Muscatell and Inagaki, 2021), we focused instead on the socially affiliative experience of sex. We investigated the interplay between immunology and motivation on sexual well-being among 158 individuals in romantic relationships. Inflammation, indexed by C-reactive protein (CRP), and sexual well-being were measured multiple times over a month. Relational approach motivation (i.e., motivation toward rewards in relationships) was measured at study entry. Results revealed significant associations between CRP and sexual satisfaction and partnered orgasms frequency for those most motivated to approach rewards with their partner. Interaction effects were replicated with relationship-focused psychological correlates of sexual well-being (e.g., touch, shared laughter, social support), but not with individual-focused outcomes (e.g., adapting to change, goal progress). This is one of the first human studies to demonstrate the body and mind coordinate to promote satisfying sexual experiences within romantic relationships.