Neuroimmune Response Research Articles

Metabolic and Inflammatory Response in Post-Traumatic Stress Disorder (PTSD): A Systematic Review on Peripheral Neuroimmune Biomarkers.

Several heterogeneous pathophysiology pathways have been hypothesized for being involved in the onset and course of Post-Traumatic Stress Disorder (PTSD). This systematic review aims to summarize the current evidence on the role of inflammation and immunological dysregulations in PTSD, investigating possible peripheral biomarkers linked to the neuroimmune response to stress. A total of 44 studies on the dysregulated inflammatory and metabolic response in subjects with PTSD with respect to controls were included. Eligibility criteria included full-text publications in the English language, human adult samples, studies involving both subjects with a clinical diagnosis of PTSD and a healthy control group. The research was focused on specific blood neuroimmune biomarkers, namely IL-1β, TNF-α, IL-6 and INF-γ, as well as on the potential harmful role of reduced antioxidant activity (involving catalase, superoxide dismutase and glutathione peroxidase). The possible role of the inflammatory-altered tryptophan metabolism was also explored. The results showed conflicting data on the role of pro-inflammatory cytokines in individuals with PTSD, and a lack of study regarding the other mediators investigated. The present research suggests the need for further studies in human samples to clarify the role of inflammation in the pathogenesis of PTSD, to define potential peripheral biomarkers.

Neuronal C-Reactive Protein/FcγRI Positive Feedback Proinflammatory Signaling Contributes to Nerve Injury Induced Neuropathic Pain.

Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that the neuronal Fc-gamma-receptor type I (FcγRI) of the dorsal root ganglion (DRG) mediates antigen-specific pain. However, the mechanisms of neuronal FcγRI in neuropathic pain remain to be explored. Here, it is found that the activation of FcγRI-related signals in primary neurons induces neuropathic pain in a rat model. This work first reveals that sciatic nerve injury persistently activates neuronal FcγRI-related signaling in the DRG, and conditional knockout (CKO) of the FcγRI-encoding gene Fcgr1 in rat DRG neurons significantly alleviates neuropathic pain after nerve injury. C-reactive protein (CRP) is increased in the DRG after nerve injury, and CRP protein of the DRG evokes pain by activating neuronal FcγRI-related signals. Furthermore, microinjection of naive IgG into the DRG alleviates neuropathic pain by suppressing the activation of neuronal FcγRI. These results indicate that the activation of neuronal CRP/FcγRI-related signaling plays an important role in the development of neuropathic pain in chronic constriction injury (CCI) rats. The findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and suggest potential therapeutic targets for neuropathic pain.

Title: Immunotherapy; a ground-breaking remedy for spinal cord injury with stumbling blocks: An overview.

Spinal cord injury (SCI) is a debilitating disorder with no known standard and effective treatment. Despite its ability to exacerbate SCI sequel by accelerating auto-reactive immune cells, an immune response is also considered essential to the healing process. Therefore, immunotherapeutic strategies targeting spinal cord injuries may benefit from the dual nature of immune responses. An increasing body of research suggests that immunization against myelin inhibitors can promote axon remyelination after SCI. However, despite advancements in our understanding of neuroimmune responses, immunoregulation-based therapeutic strategies have yet to receive widespread acceptance. Therefore, it is a prerequisite to enhance the understanding of immune regulation to ensure the safety and efficacy of immunotherapeutic treatments. The objective of the present study was to provide an overview of previous studies regarding the advantages and limitations of immunotherapeutic strategies for functional recovery after spinal cord injury, especially in light of limiting factors related to DNA and cell-based vaccination strategies by providing a novel prospect to lay the foundation for future studies that will help devise a safe and effective treatment for spinal cord injury.

Modeling integrated stress, sleep, fear and neuroimmune responses: Relevance for understanding trauma and stress-related disorders

Sleep and stress have complex interactions that are implicated in both physical diseases and psychiatric disorders. These interactions can be modulated by learning and memory, and involve additional interactions with the neuroimmune system. In this paper, we propose that stressful challenges induce integrated responses across multiple systems that can vary depending on situational variables in which the initial stress was experienced, and with the ability of the individual to cope with stress- and fear-inducing challenges. Differences in coping may involve differences in resilience and vulnerability and/or whether the stressful context allows adaptive learning and responses. We provide data demonstrating both common (corticosterone, SIH and fear behaviors) and distinguishing (sleep and neuroimmune) responses that are associated with an individual's ability to respond and relative resilience and vulnerability. We discuss neurocircuitry regulating integrated stress, sleep, neuroimmune and fear responses, and show that responses can be modulated at the neural level. Finally, we discuss factors that need to be considered in models of integrated stress responses and their relevance for understanding stress-related disorders in humans.

Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats

BackgroundWomen are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. MethodsMicroglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 μg/side, n = 5–6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 μg/side, n = 13–14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. ResultsIntra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1β (IL-1β). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1β. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. ConclusionsThese studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.

Effects of Neuropeptides on Dendritic Cells in the Pathogenesis of Psoriasis

Psoriasis is an autoimmune disease that is characterized by discolored, scaled patches of skin. Clinically, it is found that psychological factors often induce or aggravate the disease. Current research suggests that the pathogenesis of psoriasis involves the nervous and immune systems. This article reviews how neuropeptides secreted by nerve fibers affect dendritic cells in psoriasis. In this review, we describe that the neuropeptides calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide can act on dendritic cells and participate in the pathogenesis of psoriasis. These neuropeptides can affect the secretion of interleukin (IL)-12 and IL-23 by dendritic cells, which stimulate T helper (Th)1, Th17, and Th22 cells to produce immune responses and cause the manifestation of psoriasis. The application of neuropeptide inhibitors can improve the skin lesions of psoriasis, which has been confirmed in clinical trials. Therefore, neuroimmune response may be a new direction to develop new drug treatments and perspectives in the development of psoriasis.

Regulatory role of cytokines on etiology of depression in animal models: their biological mechanisms and clinical implication with physical exercise.

It has been known that chronic psychological or physical stress elicits depressive behaviors (learned helplessness, anhedonia, anxiety, etc.) and also activates to release proinflammatory cytokines in the brain. Especially, postmenopausal women under stress condition exacerbates neuroimmune systems and mood disorder. Repeated restraint stress in the ovariectomized female rats poses an immune challenge which was capable of inducing depressive-like behaviors, promoting exaggerated corticosterone responses and changing the proinflammatory cytokine expression such as interleukin (IL)-1β in the brain. Also, anti-inflammatory cytokines including IL-4 are known to regulate inflammation caused by immune response or stress challenge. Furthermore, some studies reported that physical activity can reduce stress hormones and improve personal immunity. Physical exercise has been shown to be associated with decreased symptoms of depression and anxiety, and with improved physical health, immunological function, and psychological well-being. This paper aims to discuss an overview of how stress shapes neuroimmune response and diverse roles of cytokines in animals models, acting on depressive-like behavioral changes; some beneficial aspects of exercise on stress-related disorders are addressed.

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.

A high-fat high-sugar diet and adversity early in life modulate pain outcomes at the behavioural and molecular level in adolescent rats: The role of sex

Given that adolescence is a significant period of brain plasticity and development, early life factors have the potential to alter long term outcomes. For instance, adversities such as consumption of a high-fat high-sugar (HFHS) diet and adverse childhood experiences (ACEs; e.g., neglect), and their resulting inflammation and microglial activation can influence pain outcomes by priming the neuroimmune system to overrespond to stressors. Chronic pain is highly prevalent amongst the adolescent population, with the prevalence and manifestation being sexually dimorphic. Although clinical studies show that females are twice as likely to report pain problems compared to males, the majority of pre-clinical work uses male rodents. Therefore, our aim was to examine the effects of sex, a HFHS diet, and an ACE on chronic pain outcomes following a stressor in adolescence. Rat dams were randomly assigned to a Standard or HFHS diet, with pups maintained on their respective diets then randomly allocated to a No Stress or ACE paradigm, and a Sham or Injury condition as a stressor. Results showed that early life adversities increased nociceptive sensitivity, inflammation, and microglial activation systemically and within the brain. Behaviourally, pain outcomes were more prominent in females, however the neuroimmune response was exacerbated in males. These results demonstrate the sexual dimorphism of chronic pain outcomes following early life adversities and provide insight into the mechanisms driving these changes, which will inform more targeted and effective treatment strategies for youth living with chronic pain.

Toll-like receptor 4 in the interface between neuroimmune response and behavioral alterations caused by stress

Different stressors can elicit neuroinflammatory responses modulated by innate immunity receptors, such as the family of Toll-like receptors (TLRs). The TLR4, a pattern recognition receptor (PRR), is involved in many diseases, such as inflammatory and central nervous system (CNS) diseases. Stress exposure can regulate the expression of PRRs, including TLR4, in the brain of animals, especially in the hippocampus and prefrontal cortex. Moreover, TLR4 modulates behavior and neuroinflammatory responses in the brain. In addition, to TLR4, the endocannabinoid (eCB) system plays a role in stress response and immunity, acting as a regulatory, stress-buffer system. This system is involved in many TLRs-mediated immune responses, such as microglia activation. Therefore, pharmacological approaches targeting the eCB system could modulate neuroinflammatory responses to stress by interfering with the TLR4 pathway. Although the connection between TLR4, stress, and neuroinflammation is well documented, almost no pre-clinical studies investigate the possible direct relationship between TLR4, behavior, stress, and the eCB system. Studies exploring the relationship between stress, neuroinflammation, TLR4, and the eCB system were searched using Pubmed, Web of Science, and Embase databases. Based on this search, this review is focused on the involvement of TLR4 receptors and signaling in neuroinflammation and the behavioral consequences of stress exposure. Moreover, evidence of the eCB system modulating TLR4-mediated responses was brought to the attention, pointing out a possible regulatory role of these responses by eCBs in behavior changes related to mood disorders.

Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation.

One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES) are proinflammatory chemokines that mediate neuroimmune responses to acute insults and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that 125I-labeled CCL2 and CCL5 crossed the BBB and entered the brain parenchyma. We next aimed to identify the mechanisms of 125I-CCL2 and 125I-CCL5 transport in an in situ brain perfusion model. We found that both heparin and eprodisate inhibited brain uptake of 125I-CCL2 and 125I-CCL5 in situ, whereas antagonists of their receptors, CCR2 or CCR5, respectively, did not, suggesting that heparan sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3 mg/kg lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic inflammation. Further, binding to the BBB-associated heparan sulfate is a mechanism by which both chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating neuroinflammation. SIGNIFICANCE STATEMENT: Our work demonstrates that C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 5 (CCL5) can cross the intact blood-brain barrier and that transport is robustly increased during inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each chemokine. We further show that the transport of both chemokines is inhibited by heparin and eprodisate, suggesting that CCL2/CCL5-heparan sulfate interactions could be therapeutically targeted to limit accumulation of these chemokines in the brain.

A Resilience Related Glial-Neurovascular Network Is Transcriptionally Activated after Chronic Social Defeat in Male Mice.

Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of the hippocampus in a mouse model of chronic social defeat stress. Our work revealed that in a sub-group exhibiting molecular responses upon chronic stress, the dorsal hippocampus is particularly involved in neuroimmune responses, angiogenesis, myelination, and neurogenesis, thereby enabling brain restoration and homeostasis after chronic stress. Based on these molecular insights, we applied rapamycin after the stress as a proof-of-concept pharmacological intervention and were able to substantially increase stress resilience. Our findings serve as a data resource and can open new avenues for further understanding of molecular processes underlying stress response and for targeted interventions supporting resilience.

Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on the nonreducing end of heparan sulfate (HS-NRE) within lysosomes. Enzyme deficiency results in accumulation of partially degraded HS within lysosomes throughout the body, leading to a progressive severe neurological disease. Enzyme replacement therapy has been proposed, but further evaluation of the treatment strategy is needed. Here, we used Chinese hamster ovary cells to produce a highly soluble and fully active recombinant human sulfamidase (rhSGSH). We discovered that rhSGSH utilizes both the CI-MPR and LRP1 receptors for uptake into patient fibroblasts. A single intracerebroventricular (ICV) injection of rhSGSH in MPS IIIA mice resulted in a tissue half-life of 9days and widespread distribution throughout the brain. Following a single ICV dose, both total HS and the MPS IIIA disease-specific HS-NRE were dramatically reduced, reaching a nadir 2weeks post dose. The durability of effect for reduction of both substrate and protein markers of lysosomal dysfunction and a neuroimmune response lasted through the 56days tested. Furthermore, seven weekly 148μg doses ICV reduced those markers to near normal and produced a 99.5% reduction in HS-NRE levels. A pilot study utilizing every other week dosing in two animals supports further evaluation of less frequent dosing. Finally, our dose-response study also suggests lower doses may be efficacious. Our findings show that rhSGSH can normalize lysosomal HS storage and markers of a neuroimmune response when delivered ICV.

The role of microglia and monocytes in the generation and resolution of the immune response in female and male rats

Microglia have long been thought to be responsible for the initiation of the central nervous system (CNS) immune response to pathogen exposure. However, we recently reported that depleting CNS microglia and circulating monocytes does not abrogate the sickness response in male rats or mice to bacterial endotoxin, lipopolysaccharide (LPS). How the central immune response to an endotoxin challenge is initiated and resolved in the absence of microglia and monocytes remains unclear. Here we investigated the role of microglia and monocytes in driving the behavioral, febrile and neuroimmune response to LPS using the Cx3cr1-Dtr rat model of conditional microglia/monocyte depletion, assessed if this role is similar in females and males, and examined how the response to an immune challenge might be initiated in the absence of these cells. We show that depletion of microglia and monocytes exacerbates the response to LPS at each phase of the immune cascade. Our data indicate that the changes in the central response to immune challenge may be an indirect effect of excess neutrophil expansion into the bloodstream and infiltration into peripheral organs stimulating a rapid and exacerbated cytokine and prostaglandin response to the LPS that is not curtailed by the usual negative feedback mechanisms. Thus, we show that a demonstrable immune response can be generated (and resolved) in the near complete absence of microglia and monocytes and that these cells play a regulatory role in the initiation and resolution of the response to an immune challenge, rather than being critical for it to occur.

Systemic neuroimmune responses in people with non-specific neck pain and cervical radiculopathy, and associations with clinical, psychological, and lifestyle factors.

Neuroimmune responses remain understudied in people with neck pain. This study aimed to (1) compare a broad range of systemic neuroimmune responses in people with non-specific neck pain (N = 112), cervical radiculopathy (N = 25), and healthy participants (N = 23); and (2) explore their associations with clinical, psychological and lifestyle factors. Quantification of systemic neuroimmune responses involved ex vivo serum and in vitro evoked-release levels of inflammatory markers, and characterization of white blood cell phenotypes. Inflammatory indices were calculated to obtain a measure of total immune status and were considered the main outcomes. Differences between groups were tested using analyses of covariance (ANCOVA) and multivariable regression models. Compared to healthy participants, the ex vivo pro-inflammatory index was increased in people with non-specific neck pain (β = 0.70, p = 0.004) and people with cervical radiculopathy (β = 0.64, p = 0.04). There was no difference between non-specific neck pain and cervical radiculopathy (β = 0.23, p = 0.36). Compared to non-specific neck pain, people with cervical radiculopathy showed lower numbers of monocytes (β = −59, p = 0.01). There were no differences between groups following in vitro whole blood stimulation (p ≥ 0.23) or other differences in the number and phenotype of white blood cells (p ≥ 0.07). The elevated ex vivo neuroimmune responses in people with non-specific neck pain and radiculopathy support the contention that these conditions encompass inflammatory components that can be measured systemically. There were multiple significant associations with clinical, psychological and lifestyle factors, such as pain intensity (β = 0.25) and anxiety (β = 0.23) in non-specific neck pain, visceral adipose tissue (β = 0.43) and magnification (β = 0.59) in cervical radiculopathy, and smoking (β = 0.59) and visceral adipose tissue (β = 0.52) in healthy participants. These associations were modified by sex, indicating different neuroimmune associations for females and males.

Long-term effects of prenatal stress on the development of prefrontal cortex in the adolescent offspring

Exposure to stress during pregnancy consequently prompts long-lasting effects on fetal brain development and predisposes the offspring to mental illnesses in later life. Adolescence is a vulnerable period of prefrontal cortex (PFC) development and coincident with the onset of neuropsychiatric symptoms. The medial PFC (mPFC) is the brain area that plays a significant role in emotional processing, and stress alters the function of this brain area leading to emotional disorders. Microglia not only play a role in neuroinflammatory responses but also play a crucial role in brain development, especially during synaptic development and pruning. Previous studies have revealed the long-term effects of prenatal stress (PS) on microglia activation and neuroinflammation in the hippocampus of the offspring. However, there is still a need to investigate how PS alters the mPFC development during adolescence. This study examines the effects of maternal stress during the last week of gestation on microglia activation and neuroimmune response in the mPFC of adolescent offspring. Morphological study demonstrated that PS increased the density of activated microglia in the prelimbic region of the mPFC of adolescent offspring. Besides, PS significantly increased the levels of microglia marker (Iba1), interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF) in the mPFC of the adolescent offspring. In conclusion, PS-induced microglia activation and neuroinflammation in the mPFC might increase the risk for neuropsychiatric disorders in the offspring in later years.

Pre-Molecular Assessment of Self-Processes in Neurotypical Subjects Using a Single Cognitive Behavioral Intervention Evoking Autobiographical Memory.

In the last 20 years, several contributions have been published on what concerns the conceptual and empirical connections between self-processes. However, only a limited number of publications addressed the viability of those processes to characterize mental health in neurotypical subjects with a normative pattern of neurodevelopment. Furthermore, even fewer experiments focused explicitly on the complexity of studying neurotypical phenomenal data. On the one hand, this normative pattern is commonly associated with mental health and a multifaceted self-concept and well-being. On the other hand, well-being is often related to a healthy cognitive life. However, how such intricate and complex relation between self-processes is established in neurotypical subjects requires further evidence. The novelty of this work is thus studying the first-person experience, which is correlated with the mental events aroused by a cognitive behavioral intervention. The prior methodology that led to the complete characterization of a neurotypical sample was already published by the authors, although the materials, the methods, the sample screening, and the sample size study required further explanation and exploration. This paper’s innovation is hence the phenomenological assessment of subjects’ self-regulation, which is used for mental health profiling, providing the basis for subsequent molecular typing. For that matter, a convenience sample of 128 (19–25-year-old) neurotypical young adults, healthy university students at the University of Lisbon, non-medicated and with no serious, uncontrolled, or chronic diseases, are characterized according to their cognitive functioning and self-concept. The procedure comprised (i) a mental status examination (psychological assessment) and (ii) a psychological intervention, i.e., a single cognitive behavioral intervention (intervention protocol). The psychological assessment was a standardized and structured clinical interview, which comprised the use of 4 psychological scales complementary to the classical Mental Status Examination (MSE). The intervention protocol applied a combined exercise of psychophysical training and autobiographical-self memory-recalling. The results permitted identifying and isolating four different subgroups (self awareness, self consciousness, reflective self, and pre-reflective self) in neurotypical subjects with discrete self-processes. The outcome of this study is screening four different aspects of self-reflection and the isolation between various forms of self-directed attention and their interconnections in these four mental health strata. The practical implication of this study is to fulfill an a priori pre-molecular assessment of self-regulation with separate cognitive characteristics. The reliability of these mental strata, their distinct neurophysiology, and discrete molecular fingerprint will be tested in a future publication by in silico characterization, total protein profiling, and simultaneous immunodetection of the neuropeptide and neuroimmune response of the same participants.

The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10.

The bacterial metabolite 4-methylphenol (para-cresol or p-cresol) and its derivative p-cresyl sulfate (pCS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that p-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of p-cresol, specifically its metabolite pCS that can reach the brain, in ASD remain to be investigated. The pCS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of pCS in ASD pathogenesis. In microglial cells pCS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, pCS treatment attenuates TNF-α and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-α, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of p-cresol-associated metabolites pCS and p-cresyl glucuronide (pCG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-α and TGF-β1 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with pCS-induced ASD pathogenesis.

Arsenic Activates the NLRP3 Inflammasome and Disturbs the Th1/Th2/Th17/Treg Balance in the Hippocampus in Mice.

Arsenic exerts neurotoxicity and immunomodulatory effects. Studies have shown that the nervous system is not considered to be an immune-privileged site. However, the effect of arsenic-induced neuroimmune toxicity has rarely been reported. We aimed to investigate the toxic effects of arsenic on the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and the Th1/Th2/Th17/Treg balance in the brain tissue of mice. Mice were exposed to NaAsO2 (0, 2.5, 5, and 10mg/kg) for 24h. Our results showed that 10mg/kg arsenic exposure significantly decreased brain and hippocampal indices (p < 0.05). The mRNA and protein levels of the blood‒brain barrier (BBB) tight junction protein occludin were decreased in the 5 and 10mg/kg arsenic-treated groups. Compared with those in the control group, NLRP3 protein levels in 10mg/kg arsenic-treated mice, caspase-1 protein levels in 2.5, 5, and 10mg/kg arsenic-treated mice, and IL-1β protein levels in 5 and 10mg/kg arsenic-treated mice were increased in the hippocampus (p < 0.05). In addition, arsenic induced a hippocampal inflammatory response by upregulating the mRNA levels of the proinflammatory factors IL-6 and TNF-α and downregulating the mRNA level of the anti-inflammatory factor IL-10. Moreover, arsenic decreased the mRNA levels of the Th1 and Th2 transcription factors T-bet and GATA3 and the cytokines IFN-γ and IL-4 and increased the mRNA levels of the Th17 transcription factor RORγt and the cytokine IL-22 (p < 0.05). Collectively, our study demonstrated that arsenic could induce immune-inflammatory responses by regulating the NLRP3 inflammasome and CD4+ T lymphocyte differentiation. These results provide a novel strategy to block the arsenic-induced impairment of neuroimmune responses.