RÉSUMÉ
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
Sujet(s)
Oxyde de diméthyl-diazène , Tumeurs colorectales , Sulfate dextran , Facteurs de transcription Forkhead , Acide glycyrrhizique , Rate , Lymphocytes T régulateurs , Animaux , Acide glycyrrhizique/pharmacologie , Facteurs de transcription Forkhead/métabolisme , Rate/métabolisme , Rate/anatomopathologie , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Tumeurs colorectales/induit chimiquement , Tumeurs colorectales/traitement médicamenteux , Souris , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Souris de lignée ICR , Mâle , Immunohistochimie , Protéine HMGB1/métabolismeRÉSUMÉ
Aluminum hydroxide has long been employed as a vaccine adjuvant for its safety profile, although its precise mechanism of action remains elusive. In this study, we investigated the transcriptomic responses in sheep spleen following repetitive vaccination with aluminum adjuvanted vaccines and aluminum hydroxide alone. Notably, this work represents the first exploration of the sheep spleen transcriptome in such conditions. Animals were splitted in 3 treatment groups: vaccine group, adjuvant alone group and control group. A total of 18 high-depth RNA-seq libraries were sequenced, resulting in a rich dataset which also allowed isoform-level analysis. The comparisons between vaccine-treated and control groups (V vs C) as well as between vaccine-treated and adjuvant-alone groups (V vs A) revealed significant alterations in gene expression profiles, including protein coding genes and long non-coding RNAs. Among the differentially expressed genes, many were associated with processes such as endoplasmic reticulum (ER) stress, immune response and cell cycle. The analysis of co-expression modules further indicated a correlation between vaccine treatment and genes related to ER stress and unfolded protein response. Surprisingly, adjuvant-alone treatment had little impact on the spleen transcriptome. Additionally, the role of alternative splicing in the immune response was explored. We identified isoform switches in genes associated with immune regulation and inflammation, potentially influencing protein function. In conclusion, this study provides valuable insights into the transcriptomic changes in sheep spleen following vaccination with aluminum adjuvanted vaccines and aluminum hydroxide alone. These findings shed light on the molecular mechanisms underlying vaccine-induced immune responses and emphasize the significance of antigenic components in aluminum adjuvant mechanism of action. Furthermore, the analysis of alternative splicing revealed an additional layer of complexity in the immune response to vaccination in a livestock species.
Sujet(s)
Adjuvants immunologiques , Rate , Transcriptome , Vaccination , Animaux , Rate/immunologie , Rate/métabolisme , Ovis , Analyse de profil d'expression de gènes , Vaccins/immunologie , Hydroxyde d'aluminium/immunologie , Épissage alternatifRÉSUMÉ
Haematitum is a commonly used mineral medicine. It is toxic, as recorded in the second volume of Chinese Materia Medica. Therefore, it should not be taken for a long time. In this study, the effects of Haematitum and calcined Haematitum on multiple organ injuries in mice were investigated, and the mechanism of the toxicity of the related organs was explored by metabolomics. The mice were randomly divided into the control group, Haematitum low-dose group(ZS-L group), Haematitum high-dose group(ZS-H group), and calcined Haematitum high-dose group(DZS-H group), with 12 mice in each group. Haematitum decoction was given by continuous intragastric administration for 10 days. Then the life situation was observed, and samples were taken to detect various indicators. The results showed that the ZS-H group showed obvious toxicity, with different degrees of toxicity damage in the intestinal tract,liver, spleen, and lung. ZS-L group had no toxic reaction. The toxicity of the DZS-H group was significantly reduced, and only the lung was damaged. Metabolomics technology was used to detect the lung tissue of mice in the control group and the ZS-H group, and a total of 15 kinds of significant difference metabolites were detected, mainly involved in choline metabolism in cancer, sphingolipid metabolism, and glycerophospholipid metabolism. Immunohistochemical results showed that the INSIG1 protein expression level in the lung tissue of mice in the ZS-H group was significantly higher than that in the control group. In summary, large doses and long-time use of Haematitum decoction will cause a variety of organ damage, and the same dose of calcined Haematitum is less toxic than Haematitum. In addition, a low dose of Haematitum has no obvious toxic effect. The dysfunction of lipid metabolic pathways such as sphingolipid and glycerophospholipid metabolism may be an important factor in Haematitum-induced pulmonary toxicity. This study provides a reference for further research on the mechanism of Haematitum pulmonary toxicity.
Sujet(s)
Médicaments issus de plantes chinoises , Poumon , Animaux , Souris , Médicaments issus de plantes chinoises/administration et posologie , Mâle , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolisme , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Rate/effets des médicaments et des substances chimiques , Rate/métabolisme , Défaillance multiviscérale/métabolisme , Défaillance multiviscérale/étiologie , Défaillance multiviscérale/induit chimiquement , Femelle , Métabolomique , HumainsRÉSUMÉ
Development of mRNA therapeutics necessitates targeted delivery technology, while the clinically advanced lipid nanoparticles face difficulty for extrahepatic delivery. Herein, we design highly branched poly(ß-amino ester)s (HPAEs) for efficacious organ-selective mRNA delivery through tailoring their chemical compositions and topological structures. Using an "A2+B3+C2" Michael addition platform, a combinatorial library of 219 HPAEs with varied backbone structures, terminal groups, and branching degrees are synthesized. The branched topological structures of HPAEs provide enhanced serum resistance and significantly higher mRNA expression in vivo. The terminal amine structures of HPAEs determine the organ-selectivity of mRNA delivery following systemic administration: morpholine facilitates liver targeting, ethylenediamine favors spleen delivery, while methylpentane enables mRNA delivery to the liver, spleen, and lungs simultaneously. This study represents a comprehensive exploration of the structure-activity relationship governing both the efficiency and organ-selectivity of mRNA delivery by HPAEs, suggesting promising candidates for treating various organ-related diseases.
Sujet(s)
Polymères , ARN messager , ARN messager/génétique , Animaux , Humains , Polymères/composition chimique , Souris , Nanoparticules/composition chimique , Foie/métabolisme , Rate/métabolisme , Techniques de transfert de gènes , Poumon/métabolismeRÉSUMÉ
Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.
Sujet(s)
Lupus érythémateux disséminé , Souris knockout , Animaux , Lupus érythémateux disséminé/génétique , Lupus érythémateux disséminé/métabolisme , Lupus érythémateux disséminé/anatomopathologie , Souris , Protéines mitochondriales/génétique , Protéines mitochondriales/métabolisme , Espèces réactives de l'oxygène/métabolisme , Anticorps antinucléaires , Membranes mitochondriales/métabolisme , Cellules érythroïdes/métabolisme , Cellules érythroïdes/anatomopathologie , Modèles animaux de maladie humaine , Immunoglobuline G/métabolisme , Souris de lignée C57BL , Rate/métabolisme , Rate/anatomopathologie , Protéines membranaires/génétique , Protéines membranaires/métabolisme , FemelleRÉSUMÉ
The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.
Sujet(s)
Surrénalectomie , Apoptose , Lymphopoïèse , Souris de lignée C57BL , Infarctus du myocarde , Thymus (glande) , Animaux , Thymus (glande)/anatomopathologie , Thymus (glande)/immunologie , Thymus (glande)/effets des médicaments et des substances chimiques , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/métabolisme , Infarctus du myocarde/immunologie , Infarctus du myocarde/physiopathologie , Mâle , Thymocytes/métabolisme , Thymocytes/anatomopathologie , Thymocytes/immunologie , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Glucocorticoïdes/pharmacologie , Granulocytes éosinophiles/métabolisme , Granulocytes éosinophiles/immunologie , Rate/immunologie , Rate/métabolisme , Rate/anatomopathologie , Modèles animaux de maladie humaine , Souris , Corticostérone/sangRÉSUMÉ
The impairment of the immune system by fluoride is a public health concern worldwide, yet the underlying mechanism is unclear. Both riboflavin and IL-17A are closely related to immune function and regulate the testicular toxicity of fluoride. However, whether riboflavin or IL-17A is involved in fluoride-induced immunotoxicity is unknown. Here, we first established a male ICR mouse model by treating mice with sodium fluoride (NaF) (100 mg/L) via the drinking water for 91 days. The results showed that fluoride increased the expression of the proinflammatory factors IL-1ß and IL-17A, which led to splenic inflammation and morphological injury. Moreover, the expression levels of the riboflavin transporters SLC52A2 and SLC52A3; the transformation-related enzymes RFK and FLAD1; and the key mitochondrial functional determinants SDH, COX, and ATP in the spleen were measured via real-time PCR, Western blotting, and ELISA. The results revealed that fluoride disrupted riboflavin transport, transformation, metabolism, and mitochondrial function. Furthermore, wild-type (WT) and IL-17A knockout (IL-17A-/-) C57BL/6 J male mice of the same age were treated with NaF (24 mg/kg·bw, equivalent to 100 mg/L) and/or riboflavin sodium phosphate (5 mg/kg·bw) via gavage for 91 days. Similar parameters were evaluated as above. The results confirmed that fluoride increased riboflavin metabolism through RFK but not through FLAD1. Fluoride also affected mitochondrial function and activated neutrophils (marked with Ly6g) and macrophages (marked with CD68) in the spleen. Interestingly, IL-17A partly mediated fluoride-induced riboflavin metabolism disorder and immunotoxicity in the spleen. This work not only reveals a novel toxic mechanism for fluoride but also provides new clues for exploring the physiological function of riboflavin and for diagnosing and treating the toxic effects of fluoride in the environment.
Sujet(s)
Interleukine-17 , Souris de lignée C57BL , Souris de lignée ICR , Riboflavine , Fluorure de sodium , Rate , Animaux , Mâle , Interleukine-17/métabolisme , Rate/effets des médicaments et des substances chimiques , Rate/métabolisme , Fluorure de sodium/toxicité , Souris knockout , Souris , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Transport biologiqueRÉSUMÉ
The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells' glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG's systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas.
Sujet(s)
Vaccin BCG , Glycémie , Diabète de type 1 , Fluorodésoxyglucose F18 , Tomographie par émission de positons , Rate , Diabète de type 1/traitement médicamenteux , Diabète de type 1/métabolisme , Rate/métabolisme , Rate/imagerie diagnostique , Vaccin BCG/usage thérapeutique , Humains , Animaux , Glycémie/métabolisme , Souris , Femelle , Mâle , Adulte , Souris de lignée BALB C , Adulte d'âge moyen , Tomodensitométrie , Tomographie par émission de positons couplée à la tomodensitométrieRÉSUMÉ
Nanosized ultrafine particles (UFPs) from natural and anthropogenic sources are widespread and pose serious health risks when inhaled by humans. However, tracing the inhaled UFPs in vivo is extremely difficult, and the distribution, translocation, and metabolism of UFPs remain unclear. Here, we report a label-free, machine learning-aided single-particle inductively coupled plasma mass spectrometry (spICP-MS) approach for tracing the exposure pathways of airborne magnetite nanoparticles (MNPs), including external emission sources, and distribution and translocation in vivo using a mouse model. Our results provide quantitative analysis of different metabolic pathways in mice exposed to MNPs, revealing that the spleen serves as the primary site for MNP metabolism (84.4%), followed by the liver (11.4%). The translocation of inhaled UFPs across different organs alters their particle size. This work provides novel insights into the in vivo fate of UFPs as well as a versatile and powerful platform for nanotoxicology and risk assessment.
Sujet(s)
Foie , Apprentissage machine , Nanoparticules de magnétite , Spectrométrie de masse , Taille de particule , Animaux , Souris , Nanoparticules de magnétite/composition chimique , Spectrométrie de masse/méthodes , Foie/métabolisme , Rate/métabolisme , Matière particulaire/analyse , Matière particulaire/composition chimique , Distribution tissulaireRÉSUMÉ
Objective To investigate the effect of Terminalia chebula water extract (TCWE) on the cellular immunity and PD-1/PD-L1 pathway in rats with collagen-induced arthritis (CIA). Methods SD rats were randomly divided into four groups: a control group, a CIA group, a TCWE group and a methotrexate (MTX) group, with 15 rats in each group. Except for the control group, SD rats in other groups were subcutaneously injected with type II collagen to establish the model of collagen-induced arthritis (CIA). The rats in the TCWE group were treated with 20 mg/(kg.d) TCWE and the rats in the MTX group were treated with 1.67 mg/(kg.d) MTX. After 14 days of treatment, the cartilage morphology was examined using hematoxylin-eosin (HE) staining, and splenic T lymphocyte apoptosis and Treg/Th17 cell ratio were detected by flow cytometry. The mRNA expressions of retinoid-related orphan nuclear receptor γt (RORγt), forkhead box P3 (FOXP3), PD-1 and PD-L1 in spleen were detected by reverse transcription PCR. The expression and localization of RORγt and FOXP3 were detected by immunohistochemical staining. The protein expressions of PD-1 and PD-L1 in splenic lymphocytes were detected by Western blot, and the levels of serum interleukin 17 (IL-17) and transforming growth factor ß (TGF-ß) in rats were detected by ELISA. Results Compared with CIA group, the pathological changes of cartilage and synovium were significantly alleviated in the TCWE group and the MTX group. Both the apoptosis rate of T lymphocytes in spleen and the ratio of Treg/Th17 cells increased. The expression of RORγt decreased, while the expressions of FOXP3, PD-1 and PD-L1 increased in spleen lymphocytes. The level of serum IL-17 decreased, while the level of serum TGF-ß increased. Conclusion TCWE treatment may activate PD-1/PD-L1 pathway in spleen cells to regulate cellular immunity, thus reducing cartilage injury in CIA rats.
Sujet(s)
Arthrite expérimentale , Antigène CD274 , Récepteur-1 de mort cellulaire programmée , Rat Sprague-Dawley , Rate , Terminalia , Animaux , Arthrite expérimentale/immunologie , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/métabolisme , Rate/effets des médicaments et des substances chimiques , Rate/immunologie , Rate/métabolisme , Antigène CD274/génétique , Antigène CD274/métabolisme , Récepteur-1 de mort cellulaire programmée/génétique , Récepteur-1 de mort cellulaire programmée/métabolisme , Rats , Terminalia/composition chimique , Mâle , Immunité cellulaire/effets des médicaments et des substances chimiques , Régulation positive/effets des médicaments et des substances chimiques , Extraits de plantes/pharmacologie , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/génétique , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/métabolisme , Inflammation/traitement médicamenteux , Inflammation/immunologie , Inflammation/métabolisme , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/métabolisme , Cellules Th17/immunologie , Cellules Th17/effets des médicaments et des substances chimiques , Cellules Th17/métabolismeRÉSUMÉ
Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.
Sujet(s)
Ferroptose , Macrophages , Souris de lignée C57BL , Facteur-2 apparenté à NF-E2 , Phospholipid hydroperoxide glutathione peroxidase , Transduction du signal , Rate , Animaux , Humains , Mâle , Souris , Ferroptose/effets des médicaments et des substances chimiques , Protéine-1 de type kelch associée à ECH/métabolisme , Protéine-1 de type kelch associée à ECH/génétique , Peroxydation lipidique/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Facteur-2 apparenté à NF-E2/génétique , Phospholipid hydroperoxide glutathione peroxidase/métabolisme , Phospholipid hydroperoxide glutathione peroxidase/génétique , Séquestosome-1/métabolisme , Séquestosome-1/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Rate/effets des médicaments et des substances chimiques , Rate/cytologie , Rate/métabolismeRÉSUMÉ
Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.
Sujet(s)
Lipoxines , Macrophages , Granulocytes neutrophiles , Rate , Animaux , Granulocytes neutrophiles/métabolisme , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Souris , Humains , Lipoxines/métabolisme , Lipoxines/pharmacologie , Rate/métabolisme , Rate/cytologie , Acide eicosapentanoïque/analogues et dérivés , Acide eicosapentanoïque/pharmacologie , Acide eicosapentanoïque/métabolisme , Souris de lignée C57BL , Phagocytose , Mâle , Inflammation/métabolisme , Acides heptanoïquesRÉSUMÉ
The early-life organ development and maturation shape the fundamental blueprint for later-life phenotype. However, a multi-organ proteome atlas from infancy to adulthood is currently not available. Herein, we present a comprehensive proteomic analysis of ten mouse organs (brain, heart, lung, liver, kidney, spleen, stomach, intestine, muscle and skin) at three crucial developmental stages (1-, 4- and 8-weeks after birth) acquired using data-independent acquisition mass spectrometry. We detect and quantify 11,533 protein groups across the ten organs and obtain 115 age-related differentially expressed protein groups that are co-expressed in all organs from infancy to adulthood. We find that spliceosome proteins prevalently play crucial regulatory roles in the early-life development of multiple organs, and detect organ-specific expression patterns and sexual dimorphism. This multi-organ proteome atlas provides a fundamental resource for understanding the molecular mechanisms underlying early-life organ development and maturation.
Sujet(s)
Protéome , Protéomique , Animaux , Protéome/métabolisme , Souris , Femelle , Mâle , Protéomique/méthodes , Rein/métabolisme , Rein/croissance et développement , Splicéosomes/métabolisme , Spécificité d'organe , Souris de lignée C57BL , Encéphale/métabolisme , Encéphale/croissance et développement , Foie/métabolisme , Poumon/métabolisme , Poumon/croissance et développement , Régulation de l'expression des gènes au cours du développement , Caractères sexuels , Rate/métabolisme , Rate/croissance et développementRÉSUMÉ
How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides-the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer's disease.
Sujet(s)
Monocytes , Transduction du signal , Monocytes/immunologie , Monocytes/métabolisme , Monocytes/effets des médicaments et des substances chimiques , Animaux , Souris , Microbiote/immunologie , Souris de lignée C57BL , Immunité innée , Récepteur de type Toll-2/métabolisme , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Glycoprotéines membranaires/métabolisme , Glycoprotéines membranaires/génétique , Lipopeptides/pharmacologie , Récepteurs immunologiques/métabolisme , Récepteurs immunologiques/génétique , Facteur de transcription NF-kappa B/métabolisme , Inflammation/immunologie , Facteurs de régulation d'interféron/métabolisme , Facteurs de régulation d'interféron/génétique , Mâle , Lipides , Rate/immunologie , Rate/métabolisme , Cytokines/métabolisme , FemelleRÉSUMÉ
Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from Cd47-/- mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in Cd47-/- spleens but significantly depleted in Thbs1-/- spleens. Single-cell transcriptome and flow cytometry analyses indicated that loss of CD47 is associated with accumulation and increased proliferation in spleen of Ter119-CD34+ progenitors and Ter119+CD34- committed erythroid progenitors with elevated mRNA expression of Kit, Ermap, and Tfrc. Induction of committed erythroid precursors is consistent with the known function of CD47 to limit the phagocytic removal of aged erythrocytes. Conversely, loss of thrombospondin-1 delays the turnover of aged red blood cells, which may account for the suppression of committed erythroid precursors in Thbs1-/- spleens relative to basal levels in wild-type mice. In addition to defining a role for CD47 to limit extramedullary erythropoiesis, these studies reveal a thrombospondin-1-dependent basal level of extramedullary erythropoiesis in adult mouse spleen.
Sujet(s)
Antigènes CD47 , Érythropoïèse , Rate , Thrombospondine-1 , Animaux , Antigènes CD47/métabolisme , Antigènes CD47/génétique , Thrombospondine-1/métabolisme , Thrombospondine-1/génétique , Rate/métabolisme , Souris , Souris knockout , Régulation de l'expression des gènes , Souris de lignée C57BL , Précurseurs érythroïdes/métabolismeRÉSUMÉ
Type 2 diabetes mellitus negatively affects the immune system, resulting in reduced natural killer (NK) cell activity. Vitamin D has been shown to regulate innate and adaptive immune cells. However, the effects of vitamin D on NK cells remain inconclusive, especially in the context of diabetes. We hypothesized that dietary vitamin D3 supplementation can enhance NK cell activity in diabetic mice. Therefore, we investigated the effects of dietary vitamin D3 on NK cell activity in control and diabetic mice and explored the mechanisms of NK cell activity modulation by vitamin D3. Control (CON) and diabetic mice (db/db) were randomly divided into 2 groups, then fed either a control diet (948 IU vitamin D3/kg diet, vDC) or a diet supplemented with vitamin D3 (9,477 IU vitamin D3/kg diet, vDS) for 8 weeks. Diabetic mice exhibited lower NK cell activity than control mice. The vDS group had significantly higher NK cell activity than the vDC group in both control and diabetic mice. The vDS group had a higher percentage of CD11b single-positive NK cells than the vDC group (CON-vDS 34%; db/db-vDS 30%; CON-vDC 27%; db/db-vDC 22%). The intracellular expression of splenic TGF-ß was significantly higher in the db/db group than in the CON group. Overall, vDS group had higher Bcl2 and Tbx21 mRNA expressions than the vDC group. In conclusion, the present study shows that NK cell activity is impaired under diabetic conditions, possibly due to the reduced percentage of mature NK cells. Moreover, NK activity is enhanced by dietary supplementation in both control and diabetic mice that may be associated with changes in the proportion of mature NK cells.
Sujet(s)
Cholécalciférol , Diabète de type 2 , Compléments alimentaires , Cellules tueuses naturelles , Rate , Animaux , Cellules tueuses naturelles/effets des médicaments et des substances chimiques , Cellules tueuses naturelles/métabolisme , Mâle , Cholécalciférol/pharmacologie , Cholécalciférol/administration et posologie , Rate/métabolisme , Souris , Diabète de type 2/diétothérapie , Diabète expérimental/diétothérapie , Souris de lignée C57BL , Protéines à domaine boîte-T/métabolisme , Protéines à domaine boîte-T/génétiqueRÉSUMÉ
Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial for improving patient outcomes and quality of life. Although HFpEF is the predominant heart failure type among older individuals, its prognosis is often poor owing to the lack of effective therapies. The roles of the spleen and bone marrow are often overlooked in the context of HFpEF. Recent studies suggest that the spleen and bone marrow could play key roles in HFpEF, especially in relation to inflammation and immune responses. The bone marrow can increase production of certain immune cells that can migrate to the heart and contribute to disease. The spleen can contribute to immune responses that either protect or exacerbate heart failure. Extramedullary hematopoiesis in the spleen could play a crucial role in HFpEF. Increased metabolic activity in the spleen, immune cell production and mobilization to the heart, and concomitant cytokine production may occur in heart failure. This leads to systemic chronic inflammation, along with an imbalance of immune cells (macrophages) in the heart, resulting in chronic inflammation and progressive fibrosis, potentially leading to decreased cardiac function. The bone marrow and spleen are involved in altered iron metabolism and anemia, which also contribute to HFpEF. This review presents the concept of an interplay between the heart, spleen, and bone marrow in the setting of HFpEF, with a particular focus on extramedullary hematopoiesis in the spleen. The aim of this review is to discern whether the spleen can serve as a new therapeutic target for HFpEF.
Sujet(s)
Moelle osseuse , Défaillance cardiaque , Hématopoïèse extramédullaire , Rate , Humains , Défaillance cardiaque/physiopathologie , Défaillance cardiaque/métabolisme , Hématopoïèse extramédullaire/physiologie , Rate/immunologie , Rate/métabolisme , Débit systolique/physiologie , Myocarde/métabolisme , Myocarde/anatomopathologie , Myocarde/immunologie , InflammationRÉSUMÉ
With the increasing production and demand of plastic products in life, inescapable bisphenol A (BPA) exposure results in a threat to the health of organisms. Selenium (Se) is an essential trace element for living organisms. The insufficient Se intake can cause multi-tissue organ damage. In the process of production and life, the exposure of BPA is usually accompanied by Se deficiency. In this study, the models of chicken with BPA exposure and/or Se deficiency was duplicated, the status of nitrification stress, apoptosis, necroptosis, and changes in TNF-α/FADD signaling pathways in chicken spleen were examined. At the same time, nitrification stress inhibitor and TNF-α inhibitor were introduced into MSB-1 cell model tests in vitro, indicating that BPA exposure and Se deficiency up-regulated TNF-α/FADD signaling pathway through nitrification stress, inducing necroptosis and apoptosis, and heat shock protein was also involved in this process. This study provides a new control idea for healthy poultry breeding based on Se, and also provides a new reference for toxicity control of environmental pollutants.
Sujet(s)
Poulets , Nitrification , Phénols , Rate , Facteur de nécrose tumorale alpha , Animaux , Facteur de nécrose tumorale alpha/métabolisme , Rate/effets des médicaments et des substances chimiques , Rate/métabolisme , Phénols/toxicité , Sélénium/déficit , Composés benzhydryliques/toxicité , Apoptose/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Thorium-232 (Th-232) is a promising fuel for advanced nuclear reactors. However, in case of internal human exposure to Th, there is currently no effective modality for its removal from liver and skeleton or for mitigating its effect. The FDA-approved agent, diethylenetriaminepentaacetate (DTPA), can remove Th and other actinides from blood circulation only. For the first time, a rationally-selected polyherbal hepatoprotective i.e. Liv52® (L52S), was evaluated in-combination with DTPA for its Th decorporation ability in Swiss mice. Inductively-coupled plasma mass spectroscopic analysis showed that oral administration of L52S in conjunction with DTPA significantly decreased Th burden from liver (20 %) and skeleton (33 %) as well as enhanced Th excretion (â¼2.5 folds) through urine in comparison to DTPA or L52S alone. The combinatorial therapy was found to be complementary in-action, ameliorating Th-induced tissue damage in liver, spleen, and bone more effectively than monotherapy. Furthermore, markers of liver function (alanine transaminase) and liver inflammation and fibrosis (NF-κB & keratin) further validated the beneficial effect of L52S. The human consumption of L52S for various liver disorders further supports its clinical application for Th decorporation and mitigation of its health effects.
Sujet(s)
Foie , Acide pentétique , Thorium , Animaux , Thorium/toxicité , Acide pentétique/composition chimique , Souris , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Extraits de plantes/pharmacologie , Extraits de plantes/composition chimique , Mâle , Chélateurs/pharmacologie , Chélateurs/composition chimique , Rate/effets des médicaments et des substances chimiques , Rate/métabolismeRÉSUMÉ
BACKGROUND: Integration of high throughput DNA genotyping and RNA-sequencing data enables the discovery of genomic regions that regulate gene expression, known as expression quantitative trait loci (eQTL). In pigs, efforts to date have been mainly focused on purebred lines for traits with commercial relevance as such growth and meat quality. However, little is known on genetic variants and mechanisms associated with the robustness of an animal, thus its overall health status. Here, the liver, lung, spleen, and muscle transcriptomes of 100 three-way crossbred female finishers were studied, with the aim of identifying novel eQTL regulatory regions and transcription factors (TFs) associated with regulation of porcine metabolism and health-related traits. RESULTS: An expression genome-wide association study with 535,896 genotypes and the expression of 12,680 genes in liver, 13,310 genes in lung, 12,650 genes in spleen, and 12,595 genes in muscle resulted in 4,293, 10,630, 4,533, and 6,871 eQTL regions for each of these tissues, respectively. Although only a small fraction of the eQTLs were annotated as cis-eQTLs, these presented a higher number of polymorphisms per region and significantly stronger associations with their target gene compared to trans-eQTLs. Between 20 and 115 eQTL hotspots were identified across the four tissues. Interestingly, these were all enriched for immune-related biological processes. In spleen, two TFs were identified: ERF and ZNF45, with key roles in regulation of gene expression. CONCLUSIONS: This study provides a comprehensive analysis with more than 26,000 eQTL regions identified that are now publicly available. The genomic regions and their variants were mostly associated with tissue-specific regulatory roles. However, some shared regions provide new insights into the complex regulation of genes and their interactions that are involved with important traits related to metabolism and immunity.