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Objective: To observe the changes of lung function and inflammatory factors in rat models of coal workers' pneumoconiosis at different time points. Methods: In June 2021, 96 healthy male SD rats with SPF grade were divided into 1, 3, and 6-month control group and dust staining group (coal dust group, coal silica dust group, quartz group) according to random number table method, with 8 rats in each group. After one week of adaptive feeding, a one-time non-exposed tracheal perfusion method (1 ml/ piece) was used. The dust dyeing group was given 50 g/L coal dust, coal silica mixed dust and quartz dust suspension, respectively, and the control group was given 0.9% normal saline solution. At 1, 3 and 6 months after perfusion, lung function was detected by animal lung function apparatus, then all lung tissues and alveolar lavage fluid were killed, and lung histopathological morphological changes were observed by HE staining, and the contents of interleukin (IL-1ß), IL-18, IL-4 and IL-10 in alveolar lavage fluid were detected by ELISA. One-way analysis of variance was used to compare groups. Two factors (inter-group treatment factor (4 levels) and observation time factor (3 levels) ) were used in the analysis of the effects of inter-group treatment and treatment time on related indicators. Results: HE staining results showed that coal spot appeared in the lung tissue of coal dust group, coal spot and coal silicon nodule appeared in the lung tissue of coal dust group, and silicon nodule appeared in the lung tissue of quartz group. Compared with the control group, the forced vital capacity (FVC) and forced expiratory volume at 0.2 second (FEV(0.2)) of rats in the dust staining group had interaction between the treatment and treatment time (P<0.05). With the increase of dust dyeing time, FVC and FEV(0.2) decreased significantly at 3-6 months of dust dyeing, and the maximum gas volume per minute (MVV) decreased significantly at 1-3 months of dust dyeing (P<0.05). The lowest lung function index was in quartz group, followed by coal-silica group and coal-dust group. There were statistically significant differences in the main effect and interaction effect of the pro-inflammatory factor IL-18 among all groups in treatment and treatment time (IL-18: F=70.79, 45.97, 5.90, P<0.001), and interaction existed. The highest content of inflammatory factors in alveolar lavage fluid of all dust groups was quartz group, followed by coal silica group and coal dust group. There were significant differences in the main effect and interaction effect of anti-inflammatory factors between groups and treatment time (IL-4: F=41.55, 33.01, 5.23, P<0.001, <0.001, <0.001; IL-10: F=7.46, 20.80, 2.91, P=0.002, <0.001, 0.024), and there was interaction. The highest content of anti-inflammatory factor was in quartz group, followed by coal silica group and coal dust group. Conclusion: Lung function decreased and levels of inflammatory fators increased in rat models of coal workers' pneumoconiosis, with the quartz group being the most severely damaged. Lung function is mainly impaired in thrid-six months, and the content of inflammatory factors begins to change in first-thrid months. MVV are the earliest and most obvious in lung function. IL-18 is suitable for monitoring changes in the pro-inflammatory response of coal workers' pneumoconiosis, and IL-10 is suitable for monitoring changes in anti-inflammatory response.
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Antracosis , Carbón Mineral , Modelos Animales de Enfermedad , Polvo , Pulmón , Ratas Sprague-Dawley , Animales , Ratas , Masculino , Pulmón/fisiopatología , Pulmón/patología , Antracosis/fisiopatología , Interleucina-18/metabolismo , Interleucina-4/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Cuarzo , Inflamación , Pruebas de Función RespiratoriaRESUMEN
Macrophages, pivotal components of the immune system, orchestrate host defense mechanisms in humans and mammals. Their polarization into classically activated macrophages (CAMs or M1) and alternatively activated macrophages (AAMs or M2) dictates distinct functional roles in immunity and tissue homeostasis. While the negative regulatory role of CD32b within the FC gamma receptor (FCγR) family is recognized across various immune cell types, its influence on macrophage polarization remains elusive. This study aimed to elucidate the regulatory role of CD32b in macrophage polarization and discern the differential expression markers between the M1 and M2 phenotypes following CD32b siRNA transfection. The results revealed a decrease in the CD32b levels in lipopolysaccharide (LPS)-treated M1 and an increase in interleukin-4 (IL-4)-treated M2 macrophages, as observed in macrophage Raw264.7 cells. Furthermore, CD32b siRNA transfection significantly downregulated the M2 markers (IL-10, VEGF, Arg-1, and STAT6), while upregulating the M1 markers (IL-6, NF-κB, NOS2, and STAT1) in the Raw264.7 cells. Similar findings were recapitulated in macrophage-rich adherent cells isolated from mouse spleens. Additionally, the cytopathological analysis of pleural effusions and ascitic fluids from patients with cancer revealed a positive correlation between advanced tumor stages, metastasis, and elevated CD32b levels. In conclusion, this study highlights the regulatory influence of CD32b in suppressing M1 expression and promoting M2 polarization. Moreover, heightened M2 activation and CD32b levels appear to correlate with tumor progression. A targeted CD32b blockade may serve as a novel therapeutic strategy to inhibit M2 macrophage polarization and is promising for anti-tumor intervention.
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Activación de Macrófagos , Macrófagos , Receptores de IgG , Animales , Ratones , Humanos , Macrófagos/metabolismo , Macrófagos/inmunología , Receptores de IgG/metabolismo , Células RAW 264.7 , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/inmunología , Progresión de la Enfermedad , Lipopolisacáridos/farmacología , Interleucina-4/metabolismo , Femenino , MasculinoRESUMEN
Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
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Linfocitos T CD8-positivos , Interleucina-4 , Humanos , Animales , Interleucina-4/metabolismo , Interleucina-4/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ratones Endogámicos NOD , FemeninoRESUMEN
We reported that infiltrated Ly6C+ macrophages express brain-derived neurotrophic factor (BDNF) only at the cerebral cortex infarct in a rat dMCAO model. However, the changein neuron-expressed BDNF, the niche components that induce the Ly6C+ cells to express BDNF, and the cellular sources of these components, remain unclear. In this study, immunofluorescence double staining was performed to label BDNF and Ly6C on brain sections at 3, 24, and 48 h following distal middle cerebral artery occlusion (dMCAO) of male rats, and to stain BDNF with Ly6C, IL-4R, and IL-10R. A neutralizing anti-IL-4 antibody was injected into the infarct, and the IL-4 and BDNF concentrations in the subareas of the infarct were determined using enzyme-linked immunosorbent assay. To find out the cellular sources of IL-4, the markers for microglia, T cells, and neurons were co-stained with IL-4 separately. In certain infarct subareas, the main BDNF-expressing cells shifted quickly from NeuN+ neurons to Ly6C+ cells during 24-48 h post-stroke, and the Ly6C+/BDNF+ cells mostly expressed IL-4 receptor. Following IL-4 neutralizing antibody injection, the BDNF, IL-4 protein levels, and BDNF+/Ly6C+ cells decreased significantly. The main IL-4-expressing cell type in this infarct subarea is not neuron either, but immune cells, including microglia, monocyte, macrophages, and T cells. The neurons, maintained BDNF and IL-4 expression in the peri-infarct area. In conclusion, in a specific cerebral subarea of the rat dMCAO model, IL-4 secreted by immune cells is one of the main inducers for Ly6C+ cells to express BDNF.
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Isquemia Encefálica , Factor Neurotrófico Derivado del Encéfalo , Interleucina-4 , Macrófagos , Animales , Masculino , Ratas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/inmunología , Isquemia Encefálica/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Interleucina-4/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-DawleyRESUMEN
Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK-STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously.
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Neoplasias Encefálicas , Antígenos CD40 , Glioblastoma , Interleucina-13 , Interleucina-4 , Interleucina-6 , Microambiente Tumoral , Humanos , Antígenos CD40/metabolismo , Ensayos Clínicos como Asunto , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismoRESUMEN
As terahertz (THz) technology advances, the interaction between THz radiation and the living body, particularly its effects on the immune system, has attracted extensive attention but remains poorly understood. This study firstly elucidated that exposure to 3 THz-FEL radiation markedly suppressed contact hypersensitivity reactions in mice induced by DNFB, as evidenced by a reduction in ear thickness and a discernible recovery in the Th1/Th2 cell balance. 3 THz irradiation led to cellular stress in the irradiated skin locale, increasing the levels of IL-4 and IL-10 and modulating the activity and migration of dendritic cells and mast cells. Furthermore, THz irradiation precipitated a rapid alteration in the skin lipidome, altering several categories of bioactive lipids. These findings offer new insights into the immunomodulatory effects of THz radiation on living organisms and the potential underlying mechanisms, with implications for the development of therapeutic approaches in managing skin allergic diseases.
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Interleucina-4 , Mastocitos , Piel , Radiación Terahertz , Animales , Ratones , Mastocitos/efectos de la radiación , Mastocitos/inmunología , Piel/efectos de la radiación , Interleucina-4/metabolismo , Células Dendríticas/efectos de la radiación , Células Dendríticas/inmunología , Interleucina-10/metabolismo , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/etiología , Ratones Endogámicos BALB C , Dinitrofluorobenceno , Femenino , Células Th2/efectos de la radiación , Células Th2/inmunología , Células TH1/efectos de la radiación , Células TH1/inmunologíaRESUMEN
BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.
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Hipertensión Pulmonar , Pulmón , Schistosoma mansoni , Animales , Ratones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/parasitología , Hipertensión Pulmonar/inmunología , Pulmón/parasitología , Pulmón/inmunología , Pulmón/patología , Schistosoma mansoni/inmunología , Clorhidrato de Fingolimod/farmacología , Femenino , Linfocitos T CD4-Positivos/inmunología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/patología , Modelos Animales de Enfermedad , Interleucina-4/metabolismo , Citocinas/metabolismo , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Esquistosomiasis/complicaciones , Esquistosomiasis/inmunología , Esquistosomiasis/parasitologíaRESUMEN
Keloids, characterized by excessive scar formation following dermal inflammation, pose a therapeutic challenge due to high recurrence rates. Radiation therapy, contraindicated in children, can minimize recurrence post-surgical removal. Dupilumab, which inhibits the pro-fibrotic interleukin-4/interleukin-13 axis, may effectively manage keloids when intralesional corticosteroid injections are unsuccessful. It may also prevent recurrence post-surgery in pediatric patients. This systematic review assesses the efficacy and safety of dupilumab for the treatment of keloids. Through a systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we identified and analyzed outcomes from three case reports and three case series studies, totaling 15 patients. Results indicate variable responses to treatment, including significant improvements, no clinical change, and worsening of keloid symptoms. Additional research is needed to recommend using dupilumab to treat keloids (Grade D). Treatment response variability may be linked to differences in interleukin-4/interleukin-13 activity between active and inactive keloids. Additionally, the unintended promotion of T helper 17 cell differentiation by dupilumab may worsen keloids.
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Anticuerpos Monoclonales Humanizados , Queloide , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Interleucina-13 , Interleucina-4/metabolismo , Queloide/tratamiento farmacológico , Queloide/terapia , Resultado del TratamientoRESUMEN
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
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Dermatitis Atópica , Interleucina-13 , Interleucinas , Prurigo , Prurito , Humanos , Dermatitis Atópica/metabolismo , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Dermatitis Atópica/inmunología , Prurigo/metabolismo , Prurigo/patología , Prurigo/genética , Femenino , Adulto , Masculino , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucinas/metabolismo , Interleucinas/genética , Prurito/metabolismo , Prurito/genética , Persona de Mediana Edad , Interleucina-4/metabolismo , Interleucina-4/genética , Enfermedad Crónica , Piel/metabolismo , Piel/patología , Adulto Joven , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Subunidad alfa2 del Receptor de Interleucina-13/genéticaRESUMEN
OBJECTIVE: In recent years, the clinical efficacy of medications for adenoid hypertrophy has been demonstrated. Topical nasal steroids have effects to shrink hypertrophic adenoids and improve symptoms of associated diseases. However, the mechanism which topical steroid administrations cause adenoid shrinkage remains unclear, herein, sensitivity for topical steroids in the mucosal epithelium of adenoids was evaluated histologically by comparing with tonsils. METHODS: Histological analysis was performed on adenoids and tonsils removed from 32 pediatric patients with adenoid hypertrophy. In hematoxylin-eosin-stained specimens, the morphology of the mucosal epithelium and eosinophil infiltration were evaluated. The expression of the glucocorticoid receptor (GR), interleukin (IL)-4, and IL-25 in the mucosal epithelium was evaluated, and the staining intensity was scored as 0 (none), 1 (weak), and 2 (strong). The number of eosinophils and expression scores of GR, IL-4, and IL-25 were statistically compared between adenoids and tonsils and analyzed correlations with adenoids sizes. RESULTS: Adenoids were covered with ciliated epithelium, and eosinophils in the mucosal epithelium and submucosal area was higher than tonsils (p < 0.05). GR expression in the most superficial layer of the mucosal epithelium was observed in adenoids, and the expression intensity score was higher than that in tonsils (p < 0.05). IL-4 and IL-25 were more widely expressed in the mucosal epithelium of adenoids than in tonsils, and their expression intensity scores were also higher than in tonsils (p < 0.05). A correlation was found between adenoid size and the intensity of IL-25 expression in the adenoid epithelium (p < 0.05). CONCLUSION: Eosinophilic inflammations in adenoids mucosal epithelium could be one of etiology of adenoid hypertrophy, and the GR and eosinophilic inflammation in the adenoids mucosal epithelium might be target of topical nasal steroids to shrink hypertrophic adenoids.
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Tonsila Faríngea , Eosinófilos , Hipertrofia , Tonsila Palatina , Receptores de Glucocorticoides , Humanos , Tonsila Faríngea/patología , Tonsila Faríngea/metabolismo , Receptores de Glucocorticoides/metabolismo , Masculino , Niño , Femenino , Eosinófilos/metabolismo , Preescolar , Tonsila Palatina/patología , Interleucina-17/metabolismo , Membrana Mucosa/patología , Membrana Mucosa/metabolismo , Interleucina-4/metabolismo , Epitelio/patología , Epitelio/metabolismo , Glucocorticoides , Citocinas/metabolismo , AdolescenteRESUMEN
In bone tissue engineering, biological scaffolds are designed with structural and functional properties that closely resemble the extracellular environment, aiming to establish a microenvironment conducive to osteogenesis. Macrophages hold significant potential for promoting osteogenesis and modulating the biological behavior of tumor cells. Multiple coculture experiments of macrophages and osteoblasts have demonstrated that macrophage polarization significantly impacts osteogenesis. Therefore, exploring bone biomaterials that can modulate macrophage polarization holds great clinical significance. In this study, heparin was modified with maleimide and was used as a raw material to form a hydrogel with 4-am-PEG-SH. The compound was used to polarize macrophages and promote osteogenesis after combining with interleukin 4 (IL-4) by taking advantage of the electronegativity of heparin. The results revealed overexpressed M2 macrophage-related phenotypic genes and cocultivation with MC3T3-E1 cells demonstrated the osteogenesis-promoting effect of the loaded IL-4 heparin hydrogel. Previous research reported that hydrogel loaded with IL-4 can be used as a biomaterial for osteogenesis promotion. Heparin materials used in this paper are derived from clinically anticoagulant drugs and feature a simple operation. The synthesized hydrogel effectively binds cytokines, regulates macrophages to induce osteogenesis and has many potential clinical applications.
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Diferenciación Celular , Heparina , Hidrogeles , Interleucina-4 , Macrófagos , Osteogénesis , Heparina/farmacología , Heparina/química , Animales , Interleucina-4/farmacología , Interleucina-4/metabolismo , Ratones , Osteogénesis/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Diferenciación Celular/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Células RAW 264.7RESUMEN
Atopic dermatitis (AD) is associated with chronic inflammation and an altered skin barrier. Lipids of the stratum corneum of AD patients are known to differ substantially in composition from those of healthy subjects. A reconstructed human epidermis (RHE) model has been developed in vitro in order to mimic the characteristics of AD. In this study, using this model, we compared lipid profile modifications between control RHE and RHE treated with Th2 cytokines in order to mimic AD. We focused particularly on the lipid profile of the ceramide subclasses: non-hydroxy sphingosine (NS) and esterified ω-hydroxy sphingosine (EOS), which have been reported to be clearly modified in atopic skin. RHE lipids were extracted and analysed using high-performance liquid chromatography coupled to high-resolution mass spectrometry. The following lipid profile changes were observed in Th2-cytokine-treated RHE: (i) an increase in ceramide NS composed of an unsaturated fatty acid chain; (ii) an increase in saturated ceramide NS with small total carbon content (≤40 carbon atoms), whereas NS with a higher total carbon content (≥42 carbon atoms) was decreased; and (iii) a decrease in ceramide EOS. These results are in accordance with reported lipid profiles of human atopic skin in vivo. Moreover, the in vitro model represents a useful tool to better understand the pathogenesis of AD which may be used for future screening of new effective treatments.
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Ceramidas , Citocinas , Dermatitis Atópica , Epidermis , Células Th2 , Humanos , Ceramidas/metabolismo , Ceramidas/análisis , Epidermis/metabolismo , Epidermis/efectos de los fármacos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Citocinas/metabolismo , Esfingosina/análogos & derivados , Interleucina-4/metabolismo , Modelos Biológicos , Interleucina-33/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.
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Bleomicina , Linaje de la Célula , Interleucina-4 , Pulmón , Factor de Transcripción SOX9 , Animales , Interleucina-4/metabolismo , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Ratones , Pulmón/metabolismo , Pulmón/patología , Ratones Endogámicos C57BL , Células Madre Adultas/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Envejecimiento/metabolismo , Diferenciación Celular , Transducción de Señal , Humanos , Macrófagos/metabolismoRESUMEN
Tissue engineering technology offers a promising solution for ear reconstruction; however, it faces the challenge of foreign body reaction and neocartilage malformation. This study investigates the impact of interleukin-4 (IL-4), an anti-inflammatory factor, on cartilage regeneration of hydrogel encapsulating autologous auricular chondrocytes in a rabbit subcutaneous environment. Initially, we assessed the influence of IL-4 on chondrocyte proliferation and determined the appropriate concentration using the CCK-8 test in vitro. Subsequently, we loaded IL-4 into gelatin methacryloyl (GelMA) hydrogel containing chondrocytes and measured its release profile through ELISA. The constructs were then implanted autologously into rabbits' subcutis, and after 3, 7, 14, and 28 days, cartilage matrix formation was evaluated by histological examinations, and gene expression levels were detected by qRT-PCR. Results demonstrated that IL-4 promotes chondrocyte proliferation in vitro, and maximum release from constructs occurred during the first week. In the rabbit subcutaneous implantation model, IL-4-loaded constructs (20 ng/mL) maintained a superior chondrocytic phenotype compared to controls with increased expression of anti-inflammatory factors. These findings highlight IL-4 as a potential strategy for promoting chondrogenesis in a subcutaneous environment and improving ear reconstruction.
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Condrocitos , Condrogénesis , Cartílago Auricular , Gelatina , Hidrogeles , Interleucina-4 , Ingeniería de Tejidos , Animales , Conejos , Gelatina/química , Gelatina/farmacología , Condrogénesis/efectos de los fármacos , Interleucina-4/metabolismo , Interleucina-4/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Condrocitos/metabolismo , Condrocitos/citología , Metacrilatos/química , Metacrilatos/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of ß-arrestin 1 and ß-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two ß-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two ß-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related ß-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.
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Modelos Animales de Enfermedad , Interleucina-4 , Microglía , Enfermedad de Parkinson , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Microglía/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Interleucina-4/metabolismo , Ratones , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación Oxidativa , beta-Arrestinas/metabolismo , Mitocondrias/metabolismo , Humanos , MasculinoAsunto(s)
Vesículas Extracelulares , Interleucina-4 , MicroARNs , Mucina 5AC , Moco , Mucina 5AC/metabolismo , Mucina 5AC/genética , Vesículas Extracelulares/metabolismo , Humanos , Moco/metabolismo , Interleucina-4/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Lavado Nasal (Proceso)/métodos , AnimalesRESUMEN
Objective: To identify potential therapeutic targets of chronic sinusitis with nasal polyps (CRSwNP) through proteomics screening of and verify its effectiveness experimentally. Methods: The nasal tissue samples were collected from patients undergoing surgical treatment in the Department of Otorhinolaryngology, Head and Neck Surgery in Yuhuangding Hospital of Yantai from June 2010 to December 2021, including 69 patients with CRSwNP and 39 patients in the control group. Tissue samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-independent acquisition (DIA) mode to find differentially expressed proteins. Bioinformatics tools were employed to analyze the functions of differentially expressed proteins. The expression of hematopoietic cell kinase (HCK) in nasal tissues of patients with CRSwNP was further confirmed by qPCR and western blot. The mouse model of CRSwNP was established and treated with HCK inhibitor. The levels of inflammatory factors IgE, IL-4 and IL-5 in serum of CRSwNP mice, both treated and untreated with HCK inhibitors, were detected by enzyme-linked immunosorbent assay (ELISA) across different experimental groups. The experimental data were analyzed by Graphpad Prism 9 software. Results: DIA analysis identified 1 850 differential proteins, including 760 up-regulated proteins and 1 090 down-regulated proteins. Weighted correlation network analysis (WGCNA) correlation analysis of phenotypic data such as cell count and CT score with the results of genomics indemnified 575 proteins of MEBrown module which intersected with 35 kinases further screened from 1 850 differential proteins, yielding eight protein kinases: HCK, SYK, PDK2, FGR, PRKCB, ROR1, CAMK1 and GRK6. qPCR showed that the expression of HCK in CRSwNP was significantly higher than that in the control group (P<0.05). Further experiments in mice confirmed that the secretion of IgE, IL-4 and IL-5 in the serum of CRSwNP group was significantly higher than the control group (all P<0.05), indicating successful model establishment. The intervention of HCK significantly decreased the secretion of IgE, IL-4 and IL-5 in serum of mice (all P<0.05). Conclusion: The HCK inhibitor can reduce the inflammatory index of mice with CRSwNP, and HCK is a potential therapeutic target of CRSwNP.
Asunto(s)
Modelos Animales de Enfermedad , Pólipos Nasales , Proteómica , Sinusitis , Sinusitis/metabolismo , Animales , Ratones , Proteómica/métodos , Enfermedad Crónica , Pólipos Nasales/metabolismo , Humanos , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Espectrometría de Masas en Tándem , Inmunoglobulina E/sangre , Cromatografía LiquidaRESUMEN
Objective:The purpose of this study is to explore the expression of prostacyclin receptorï¼IPï¼ in patients with chronic rhinosinusitisï¼CRSï¼ and its possible association with type 2 inflammation. Methods:HE staining was used to observe the morphological changes of nasal mucosa, qRT-PCR was used to detect the expression of IP in polyps and nasal mucosa, and IHC was used to detect the expression of IP, IL-4, IL-5 and IL-13 in polyps and nasal mucosa. Results:Compared with the control group, the nasal mucosa of patients with various types of CRS was obviously thickened, accompanied by inflammatory cell infiltration and gland hyperplasia. The statistical results of IHC showed that the expression levels of IL-4, IL-5 and IL-13 in CRS group were significantly higher than those in control groupï¼P<0.05ï¼, and the IP expression in control group was significantly higher than that in ECRS group and non-ECRS groupï¼P<0.05ï¼. The IP expression in ECRS group was negatively correlated with IL-4, IL-5 and IL-13. The results of qRT-PCR showed that the expression of IP mRNA in control group was significantly higher than that in ECRS group and non-ECRS groupï¼P<0.05ï¼. Conclusion:IL-4, IL-5 and IL-13 are highly expressed in the nasal mucosa of CRS patients, while IP is poorly expressed in the nasal mucosa of CRS patients, and IP is negatively correlated with IL-4, IL-5 and IL-13, suggesting that IP is related to the occurrence and development of type 2 inflammation and may be a potential therapeutic target for CRS patients.
Asunto(s)
Inflamación , Mucosa Nasal , Pólipos Nasales , Receptores de Epoprostenol , Rinosinusitis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Crónica , Inflamación/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasales/metabolismo , Receptores de Epoprostenol/metabolismo , Rinosinusitis/metabolismoRESUMEN
Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1ß2 (LTα1ß2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1ß2-lymphotoxin ß receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.