Immune Homeostasis Research Articles

A transcription factor ATF3 involves in the phagocytosis of granulocytes in oyster Crassostrea gigas

Phagocytosis is a major cellular mechanism for mollusk granulocytes to eliminate nonself substances and dead cells, and thus to preserve the immune homeostasis. The knowledge of the regulatory mechanisms controlling phagocytic capacity is vital to understanding the immune system. In the present study, an ATF3 homolog (CgATF3) with a typical bZIP domain was identified in the Pacific oyster Crassostrea gigas. Its highly conserved bZIP domain consisted of two structural features, a basic region for DNA binding and a leucine zipper region for dimerization. Its transcript was found to be abundantly expressed in haemocytes, which was induced by Vibrio splendidus stimulation and recombinant CgTNF-2 treatment, along with an increase of its protein content in the nucleus. Moreover, CgATF3 showed a consistent and specific high expression in granulocytes, and CgATF3+ granulocytes were characterized morphologically by the largest diameter, smaller nucleus to cytoplasmic ratio, and abundant cytoplasmic granules, and functionally by a higher capacity for phagocytosis. When CgATF3 expression was inhibited by RNAi, the expression levels of CgRab1, CgRab33 and CgCathepsin L1, as well as the phagocytic rate and index of granulocytes all decreased after V. splendidus stimulation. These results together demonstrated the involvement of CgATF3 in regulating the expressions of Rabs and Cathepsin L1, as well as the phagocytosis of granulocytes in oyster C. gigas.

Regulatory T cells administration reduces anxiety-like behavior in mice submitted to chronic restraint stress.

Major depression disorder (MDD) and anxiety are common mental disorders that significantly affect the quality of life of those who suffer from them, altering the person's normal functioning. From the biological perspective, the most classical hypothesis explaining their occurrence relies on neurotransmission and hippocampal excitability alterations. However, around 30% of MDD patients do not respond to medication targeting these processes. Over the last decade, the involvement of inflammatory responses in depression and anxiety pathogenesis has been strongly acknowledged, opening the possibility of tackling these disorders from an immunological point of view. In this context, regulatory T cells (Treg cells), which naturally maintain immune homeostasis by suppressing inflammation could be promising candidates for their therapeutic use in mental disorders. To test this hypothesis, C57BL/6 adult male mice were submitted to classical stress protocols to induce depressive and anxiety-like behavior; chronic restriction stress (CRS), and chronic unpredictable stress (CUS). Some of the stressed mice received a single adoptive transfer of Treg cells during stress protocols. Mouse behavior was analyzed through the open field (OFT) and forced swim test (FST). Blood and spleen samples were collected for T cell analysis using cell cytometry, while brains were collected to study changes in microglia by immunohistochemistry. Mice submitted to CRS and CUS develop anxiety and depressive-like behavior, and only CRS mice exhibit lower frequencies of circulating Treg cells. Adoptive transfer of Treg cells decreased anxiety-like behavior in the OFT only in CRS model, but not depressive behavior in FST in neither of the two models. In CRS mice, Treg cells administration lowered the number of microglia in the hippocampus, which increased due this stress paradigm, and restored its arborization. However, in CUS mice, Treg cells administration increased microglia number with no significant effect on their arborization. Our results for effector CD4+ T cells in the spleen and microglia number and morphology in the hippocampus add new evidence in favor of the participation of inflammatory responses in the development of depressive and anxiety-like behavior and suggest that the modulation of key immune cells such as Treg cells, could have beneficial effects on these disorders.

Ratio of immune indices in women of the semi-arid region

Environmental and climatic factors have a significant impact on the immune system, shaping its composition and functions. The semiarid region of Aleppo, characterized by hot, dry summers and moderate, wet and cold winters, is also characterized by environmental pollution such as air pollutants and industrial chemicals. The interaction of these environmental and climatic factors can impair immune function by causing inflammatory responses, compromising the integrity of immune cells, and impairing the body’s ability to mount an effective immune response. To date, the physiological characteristics of the parameters of the human blood system and the development of physiological reactions of adaptive immune homeostasis depending on the territory of residence have not been sufficiently studied. In this work, we studied the state of immune indices in women living in the semi-arid region. Thirty women aged from 20 to 60 years without chronic and acute diseases were examined. Immunocompetence was assessed using white blood cell count, lymphocyte subset analysis and calculation of immune indices including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), systemic inflammatory response index (SIRI), immunoregulatory index (CD4+/ CD8+) and lymphoproliferation ratio and apoptosis (CD10+/CD95+ and CD71+/CD95+). The results of the analysis showed that the median NLR was 2.18 (1.50-2.90), LMR 6.66 (5.47-8.87), SIRI 0.64 (0.45-0.98), immunoregulatory index 0.99 (0.84-1.27) and the ratio of lymphoproliferation processes to apoptosis (CD10+/ CD95+ and CD71+/CD95+) 0.95 (0.65-1.29) and 0.94 (0.78-1.11), respectively, which indicates a stressful state of immune homeostasis and signs of premature aging of the immune system. Neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), systemic inflammatory response index (SIRI), immunoregulatory index (CD4+/CD8+) and lymphoproliferation-apoptosis ratio were determined. (CD10+/ CD95+ and CD71+/ CD95+) in the examined women of the semiarid climate zone of residence, emphasizes the stressful level of immune homeostasis. The results obtained highlight the need for systematic individual biomedical monitoring to maintain immune homeostasis in populations inhabiting similar environmental conditions.

The Bioactive Interface of Titanium Implant with Both Anti-Oxidative Stress and Immunomodulatory Properties for Enhancing Osseointegration under Diabetic Condition.

The poor implant-osseointegration under diabetic condition remains a challenge to be addressed urgently. Studies have confirmed that the diabetic pathological microenvironment is accompanied by excessive oxidative stress, imbalanced immune homeostasis, and persistent chronic inflammation, which seriously impairs the osteogenic process. Herein, a multifunctional bioactive interface with both anti-oxidative stress and immunomodulatory properties is constructed on titanium implants. Briefly, manganese dioxide nanosheets are coated onto mesoporous polydopamine nanoparticles loaded with carbon monoxide gas precursor, namely MnO2-CO@MPDA NPs, and then they are integrated on the titanium implant to obtain MCM-Ti. In the simulated diabetic microenvironment, under the action of MnO2 nanoenzymes, MCM-Ti can effectively eliminate intracellular reactive oxygen species while alleviating hypoxic state. Interestingly, the microenvironment mediates the responsive release of CO gas, which effectively drives macrophages toward M2 polarization, thereby ameliorating inflammatory response. The potential mechanism is that CO gas up-regulates the expression of heme oxygenase-1, further activating the Notch/Hes1/Stat3 signaling pathway. Furthermore, the conditioned medium derived from macrophages on MCM-Ti surface significantly enhances the osteogenic differentiation of BMSCs. In a type 2 diabetic rat model, MCM-Ti implant effectively alleviates the accompanying inflammation and enhances the osseointegration through the synergistic effects of resisting oxidative stress and remodeling immune homeostasis.

The influence of iron nutrition on the development of intestine and immune cell divergency in neonatal pigs

BackgroundAppropriate iron supplementation is essential for neonatal growth and development. However, there are few reports on the effects of iron overload on neonatal growth and immune homeostasis. Thus, the aim of this study was to investigate the effects of iron nutrition on neonatal growth and intestinal immunity by administering different levels of iron to neonatal pigs.ResultsWe found that iron deficiency and iron overload resulted in slow growth in neonatal pigs. Iron deficiency and iron overload led to down-regulation of jejunum intestinal barrier and antioxidant marker genes, and promoted CD8+ T cell differentiation in jejunum and mesenteric lymph nodes (MLN) of pigs, disrupting intestinal health. Moreover, iron levels altered serum iron and tissue iron status leading to disturbances in redox state, affecting host innate and adaptive immunity.ConclusionsThese findings emphasized the effect of iron nutrition on host health and elucidated the importance of iron in regulating redox state and immunity development. This study provided valuable insights into the regulation of redox state and immune function by iron metabolism in early life, thus contributing to the development of targeted interventions and nutritional strategies to optimize iron nutrition in neonates.

Vps34 sustains Treg cell survival and function via regulating intracellular redox homeostasis.

The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.

Probiotics in miRNA-Mediated Regulation of Intestinal Immune Homeostasis in Pigs: A Physiological Narrative.

The microbiota plays a crucial role in maintaining the host's intestinal homeostasis, influencing numerous physiological functions. Various factors, including diet, stress, and antibiotic use, can lead to such imbalances. Probiotics have been shown to restore the microbiota, contributing to maintaining this balance. For instance, the weaning stage in piglets is crucial; this transition can cause unfavorable changes that may contribute to the onset of diarrhea. Probiotic supplementation has increased due to its benefits. However, its mechanism of action is still controversial; one involves the regulation of intestinal immunity. When recognized by immune system cells through membrane receptors, probiotics activate intracellular signaling pathways that lead to changes in gene expression, resulting in an anti-inflammatory response. This complex regulatory system involves transcriptional and post-transcriptional mechanisms, including the modulation of various molecules, emphasizing microRNAs. They have emerged as important regulators of innate and adaptive immune responses. Analyzing these mechanisms can enhance our understanding of probiotic-host microbiota interactions, providing insights into their molecular functions. This knowledge can be applied not only in the swine industry, but also in studying microbiota-related disorders. Moreover, these studies serve as animal models, helping to understand better conditions such as inflammatory bowel disease and other related disorders.

Arsenic-induced transition of thymic inflammation-to-fibrosis involves Stat3-Twist1 interaction: Melatonin to the rescue.

Groundwater arsenic is a notorious toxicant and exposure to environmentally relevant concentrations persists as a healthcare burden across the world. Arsenic has been reported to jeopardize the normal functioning of the immune system, but there are still gaps in the understanding of thymic T cell biology. Immunotoxic influence of arsenic in thymic integrity demands a potent restorative molecule. The objectives of this study were to examine key signaling cross-talks associated with arsenic-induced immune alterations in the thymus and propose melatonin as a potential candidate against immunological complications arising from arsenic exposure. Swiss albino mice were exposed to sodium arsenite (0.05 mg/L; in drinking water) and melatonin (IP:10 mg/kg BW) for 28 days. Melatonin successfully protected thymus from arsenic-mediated tissue degeneration and maintained immune homeostasis including T cell maturation and proliferation by mitigating oxidative stress through Nrf2 upregulation. Additionally, melatonin exerted ameliorative effect against arsenic-induced apoptosis and inflammation by inhibiting p53-mediated mitochondrial cell death pathway and NF-κB-p65/STAT3-mediated proinflammatory pathway, respectively. For the first time, we showed that arsenic-induced profibrotic changes were inhibited by melatonin through targeting of inflammation-associated EMT. Our findings clearly demonstrate that melatonin can be a viable and promising candidate in combating arsenic-induced immune toxicity with no collateral damage, making it an important research target.

RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair.

Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (ring finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 (signal transducer and activator of transcription 1) activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.

Microbial and transcriptional response of Acropora valida and Turbinaria peltata to Vibrio coralliilyticus challenge: insights into corals disease resistance

BackgroundCoral diseases are significant drivers of global coral reef degradation, with pathogens dominated by Vibrio coralliilyticus playing a prominent role in the development of coral diseases. Coral phenotype, symbiotic microbial communities, and host transcriptional regulation have been well-established as factors involved in determining coral disease resistance, but the underlying mechanisms remain incompletely understood.MethodsThis study employs high-throughput sequencing to analyse the symbiotic microbial and transcriptional response of the hosts in order to evaluate the disease resistance of Acropora valida and Turbinaria peltata exposed to Vibrio coralliilyticus.ResultsA. valida exhibited pronounced bleaching and tissue loss within 7 h of pathogen infection, whereas T. peltata showed no signs of disease throughout the experiment. Microbial diversity analyses revealed that T. peltata had a more flexible microbial community and a higher relative abundance of potential beneficial bacteria compared to A. valida. Although Vibrio inoculation resulted in a more significant decrease in the Symbiodiniaceae density of A. valida compared to that of T. peltata, it did not lead to recombination of the coral host and Symbiodiniaceae in either coral species. RNA-seq analysis revealed that the interspecific differences in the transcriptional regulation of hosts after Vibrio inoculation. Differentially expressed genes in A. valida were mainly enriched in the pathways associated with energy supply and immune response, such as G protein-coupled receptor signaling, toll-like receptor signaling, regulation of TOR signaling, while these genes in T. peltata were mainly involved in the pathway related to immune homeostasis and ion transport, such as JAK-STAT signaling pathway and regulation of ion transport.ConclusionsPathogenic challenges elicit different microbial and transcriptional shifts across coral species. This study offers novel insights into molecular mechanisms of coral resistance to disease.

Quercetin intervention mitigates small intestinal damage and immunologic derangement induced by polystyrene nanoplastics: Insights from multi-omics analysis in mice

Nanoplastics (NPs), which belong to emerging environmental pollutants, threaten environmental sustainability and human health. Despite recent studies have reported that NPs damage the gastrointestinal tract and immune homeostasis, the underlying mechanisms remain unclear. Polyphenols have been found to promote NPs excretion by interacting with intestinal flora (IF). However, the potential mechanisms and action targets of this are still poorly understood. To address these knowledge gaps, we investigated the impact of quercetin and three concentrations of polystyrene nanoplastics (PS-NPs) in mice using an integrated phenotypic and multi-omics analysis. Our findings demonstrated that PS-NPs accumulate within the intestine, resulting in impairments to intestinal tissue and barrier function, as well as disturbing the expression of immune-response small intestinal genes and composition of IF. Exposure to PS-NPs significantly elevate the level of intestinal IgG and CD20+ B cells, while inhibiting T cells activation. Furthermore, PS-NPs could induce systemic immune and serum insulin level disorders. Quercetin might mitigate PS-NPs-induced intestinal damage and immune disorders though reversing IF disorders, gene expression changes, and their interaction.

Identification and Functional Analysis of Adipokinetic Hormone Receptor in Ostrinia furnacalis Guenée Larvae Parasitized by Macrocentrus cingulum.

As a typical G protein-coupled receptor, the adipokinetic hormone receptor (AKHR) has seven transmembrane domains (TMDs), and its structure and function are similar to the gonadotropin-releasing hormone receptor (GnRHR) in vertebrates. However, there is a dearth of information on other components of the AKHR signaling pathway and how it functions in the interaction between insect hosts and parasitoids. In this study, we cloned and analyzed the multifunctional Ostrinia furnacalis AKHR (OfAKHR) cDNA (GenBank accession number MF797868). OfAKHR has a 2206 bp full-length cDNA, which includes an open reading frame containing 1194 bp. OfAKHR contains the typical seven TMDs, and a "DRY" motif. OfAKHR has the highest relative expression in the fat body and the fifth instar larvae. The results revealed that ApoLpⅢ, PPO2, GS, TPS, Cecropin, and Moricin decreased the transcription levels from 48 to 72 h after the knockdown of OfAKHR expression by dsOfAKHR injection in the fourth instar O. furnacalis larvae. The parasitization of Macrocentrus cingulum selectively upregulated the expression levels of nutrition metabolism and immune-related genes in parasitized O. furnacalis larvae, stimulated lysozyme activity, and obviously raised the concentrations of triglyceride and trehalose in the hemolymph of O. furnacalis larvae. However, they inhibited the activities of PO and trehalase. This study is conducive to a deeper cognition of the roles of OfAKHR in nutrition and immune homeostasis, coevolution, and coexistence between parasitic wasps and hosts. It also sheds light on the potential as the target of pest control reagents.

Neurturin GF Enhances the Acute Cytokine Response of Inflamed Skin

Epidermal keratinocytes, immune cells and sensory nerves all contribute to immune balance and skin homeostasis. Keratinocyte release of growth factors, neuromodulators and immune activators is particularly important because each can evoke local (skin) and systemic (i.e., immune and neural) responses that can initiate and exacerbate skin pathophysiology. From studies of skin and neural growth factors, we hypothesized that neurturin (Nrtn), a member of the glial cell line-derived neurotrophic factor (GDNF) family that is expressed in skin, has particular importance in this process. Here we examine how elevation of Nrtn in skin keratinocytes impacts early cytokine expression in response to complete Freund's adjuvant (CFA)-mediated inflammation. Mice that overexpress Nrtn in keratinocytes (NrtnOE mice) and WT mice injected with Nrtn exhibit an enhanced level of TNFα and IL-1β cytokines in the skin, a response previously shown to support healing. In vitro assays suggest one source of the Nrtn-induced TNFα increase is from keratinocytes, which are shown to express Nrtn and mRNAs encoding the Nrtn receptors GFRα2, Ret, Itgβ1 and NCAM. These findings support the contribution of keratinocyte-derived Nrtn as an autocrine/paracrine factor that acts as a first line defense molecule that regulates the initial cytokine response to inflammatory challenge.

E3 Ubiquitin Ligase RNF13 Suppresses TLR Lysosomal Degradation by Promoting LAMP-1 Proteasomal Degradation.

As a highly organized system, endo-lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo-lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo-lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll-like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48-linked polyubiquitination of LAMP-1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP-1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP-1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs.

Epigenetic regulation of human FOXP3+ Tregs: from homeostasis maintenance to pathogen defense.

Regulatory T cells (Tregs), characterized by the expression of Forkhead Box P3 (FOXP3), constitute a distinct subset of T cells crucial for immune regulation. Tregs can exert direct and indirect control over immune homeostasis by releasing inhibitory factors or differentiating into Th-like Treg (Th-Treg), thereby actively contributing to the prevention and treatment of autoimmune diseases. The epigenetic regulation of FOXP3, encompassing DNA methylation, histone modifications, and post-translational modifications, governs the development and optimal suppressive function of Tregs. In addition, Tregs can also possess the ability to maintain homeostasis in diverse microenvironments through non-suppressive mechanisms. In this review, we primarily focus on elucidating the epigenetic regulation of Tregs as well as their multifaceted roles within diverse physiological contexts while looking forward to potential strategies involving augmentation or suppression of Tregs activity for disease management, particularly in light of the ongoing global COVID-19 pandemic.

CD71 + erythroid cells promote intestinal symbiotic microbial communities in pregnancy and neonatal period

BackgroundThe establishment of microbial communities in neonatal mammals plays a pivotal role in shaping their immune responses to infections and other immune-related conditions. This process is influenced by a combination of endogenous and exogenous factors. Previously, we reported that depletion of CD71 + erythroid cells (CECs) results in an inflammatory response to microbial communities in newborn mice.ResultsHere, we systemically tested this hypothesis and observed that the small intestinal lamina propria of neonatal mice had the highest frequency of CECs during the early days of life. This high abundance of CECs was attributed to erythropoiesis niches within the small intestinal tissues. Notably, the removal of CECs from the intestinal tissues by the anti-CD71 antibody disrupted immune homeostasis. This disruption was evident by alteration in the expression of antimicrobial peptides (AMPs), toll-like receptors (TLRs), inflammatory cytokines/chemokines, and resulting in microbial dysbiosis. Intriguingly, these alterations in microbial communities persisted when tested 5 weeks post-treatment, with a more notable effect observed in female mice. This illustrates a sex-dependent association between CECs and neonatal microbiome modulation. Moreover, we extended our studies on pregnant mice, observing that modulating CECs substantially alters the frequency and diversity of their microbial communities. Finally, we found a significantly lower proportion of CECs in the cord blood of pre-term human newborns, suggesting a potential role in dysregulated immune responses to microbial communities in the gut.ConclusionsOur findings provide novel insights into pivotal role of CECs in immune homeostasis and swift adaptation of microbial communities in newborns. Despite the complexity of the cellular biology of the gut, our findings shed light on the previously unappreciated role of CECs in the dialogue between the microbiota and immune system. These findings have significant implications for human health.9S5HPFpJwLA9vyqyoAGSTRVideo

Investigations on the Ability of the Insular Cortex to Process Peripheral Immunosuppression

The brain and immune system communicate through complex bidirectional pathways, but the specificity by which the brain perceives or even remembers alterations in immune homeostasis is still poorly understood. Recent data revealed that immune-related information under peripheral inflammatory conditions, termed as “immunengram”, were represented in specific neuronal ensembles in the insular cortex (IC). Chemogenetic reactivation of these neuronal ensembles was sufficient to retrieve the inflammatory stages, indicating that the brain can store and retrieve specific immune responses. Against this background, the current approach was designed to investigate the ability of the IC to process states of immunosuppression pharmacologically induced by the mechanistic target of rapamycin (mTOR) inhibitor rapamycin. We here show that the IC perceives the initial state of immunosuppression, reflected by increased deep-brain electroencephalography (EEG) activity during acute immunosuppressive drug treatment. Following an experienced period of immunosuppression, though, diminished splenic cytokine production as formerly induced by rapamycin could not be reinstated by nonspecific chemogenetic activation or inhibition of the IC. These findings suggest that the information of a past, or experienced status of pharmacologically induced immunosuppression is not represented in the IC. Together, the present work extends the view of immune-to-brain communication during the states of peripheral immunosuppression and foster the prominent role of the IC for interoception.

Synthesis and Thermodynamic Evaluation of Sialyl-Tn MUC1 Glycopeptides Binding to Macrophage Galactose-Type Lectin.

Interactions between the tumor-associated carbohydrate antigens of Mucin 1 (MUC1) and the carbohydrate-binding proteins, lectins, often lead to the creation of a pro-tumor microenvironment favoring tumor initiation, progression, metastasis, and immune evasion. Macrophage galactose binding lectin (MGL) is a C-type lectin receptor found on antigen-presenting cells that facilitates the uptake of carbohydrate antigens for antigen presentation, modulating the immune response homeostasis, autoimmunity, and cancer. Considering the crucial role of tumor-associated forms of MUC1 and MGL in tumor immunology, a thorough understanding of their binding interaction is essential for it to be exploited for cancer vaccine strategies. The synthesis of MUC1 glycopeptide models carrying a single or multiple Tn and/or sialyl-Tn antigen(s) is described. A novel approach for the sialyl-Tn threonine building block suitable for the solid phase peptide synthesis was developed. The thermodynamic profile of the binding interaction between the human MGL and MUC1 glycopeptide models was analyzed using isothermal titration calorimetry. The measured dissociation constants for the sialyl-Tn-bearing peptide epitopes were consistently lower compared to the Tn antigen and ranged from 10 μM for mono- to 1 μM for triglycosylated MUC1 peptide, respectively. All studied interactions, regardless of the glycan's site of attachment or density, exhibited enthalpy-driven thermodynamics.

Short-chain fatty acids ameliorate imiquimod-induced skin thickening and IL-17 levels and alter gut microbiota in mice: a metagenomic association analysis

Short-chain fatty acids (SCFAs) have been proposed to have anti-inflammatory effects and improve immune homeostasis. We aimed to examine the effects of SCFAs on skin phenotype, systemic inflammation, and gut microbiota in mice with psoriasis-like inflammation. Imiquimod (IMQ)-treated C57BL/6 mice served as the study model. We conducted a metagenomic association study of IMQ-mice treated with SCFAs or anti-IL-17 antibody using whole-genome shotgun sequencing. The associations among SCFA supplements, skin thickness, circulating inflammatory profiles, and fecal microbiota profiles were investigated. The microbiome study was performed using pipelines for phylogenetic analysis, functional gene analysis, and pathway analysis. In IMQ-treated mice, there were increases in skin thickness and splenic weight, as well as unique fecal microbial profiles. SCFAs ameliorated IMQ-induced skin thickening, splenic weight gain, and serum IL-17F levels, with results that were comparable with those receiving anti-IL-17 treatment. IMQ-treated mice receiving SCFAs had greater microbial diversity than mice treated with IMQ alone. SCFAs and anti-IL17 treatment were associated with alteration of gut microbiota, with increased prevalences of Oscillospiraceae and Lachnopiraceae and decreased prevalences of Muribaculaceae and Bacteroides, which have been predicted to be associated with increased glycan degradation, phenylalanine metabolism, and xylene degradation. SCFAs may mitigate IMQ-induced skin thickening and IL-17F levels and alter fecal microbiota profiles in IMQ-treated mice.

The Role of Viruses in the Pathogenesis of Immune-Mediated Gastro-Intestinal Diseases.

Immune-mediated gastrointestinal (GI) diseases, including achalasia, celiac disease, and inflammatory bowel diseases, pose significant challenges in diagnosis and management due to their complex etiology and diverse clinical manifestations. While genetic predispositions and environmental factors have been extensively studied in the context of these conditions, the role of viral infections and virome dysbiosis remains a subject of growing interest. This review aims to elucidate the involvement of viral infections in the pathogenesis of immune-mediated GI diseases, focusing on achalasia and celiac disease, as well as the virome dysbiosis in IBD. Recent evidence suggests that viral pathogens, ranging from common respiratory viruses to enteroviruses and herpesviruses, may trigger or exacerbate achalasia and celiac disease by disrupting immune homeostasis in the GI tract. Furthermore, alterations in the microbiota and, specifically, in the virome composition and viral-host interactions have been implicated in perpetuating chronic intestinal inflammation in IBD. By synthesizing current knowledge on viral contributions to immune-mediated GI diseases, this review aims to provide insights into the complex interplay between viral infections, host genetics, and virome dysbiosis, shedding light on novel therapeutic strategies aimed at mitigating the burden of these debilitating conditions on patients' health and quality of life.