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1.
Int J Biol Sci ; 20(8): 3094-3112, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38904012

RESUMEN

Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14Cre/+-IL-38f/f ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14Cre/+-IL-38f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4+T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.


Asunto(s)
Movimiento Celular , Dermatitis Atópica , Células de Langerhans , Animales , Dermatitis Atópica/metabolismo , Células de Langerhans/metabolismo , Ratones , Ratones Noqueados , Interleucina-1/metabolismo , Queratinocitos/metabolismo , Dinitrofluorobenceno , FN-kappa B/metabolismo , Interleucinas/metabolismo
2.
Cell Death Dis ; 14(3): 185, 2023 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-36882395

RESUMEN

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczema-like skin lesions, dry skin, severe itching, and recurrent recurrence. The whey acidic protein four-disulfide core domain gene WFDC12 is highly expressed in skin tissue and up-regulated in the skin lesions of AD patients, but its role and relevant mechanism in AD pathogenesis have not been studied yet. In this study, we found that the expression of WFDC12 was closely related to clinical symptoms of AD and the severity of AD-like lesions induced by DNFB in transgenic mice. WFDC12-overexpressing in the epidermis might promote the migration of skin-presenting cells to lymph nodes and increase Th cell infiltration. Meanwhile, the number and ratio of immune cells and mRNA levels of cytokines were significantly upregulated in transgenic mice. In addition, we found that ALOX12/15 gene expression was upregulated in the arachidonic acid metabolism pathway, and the corresponding metabolite accumulation was increased. The activity of epidermal serine hydrolase decreased and the accumulation of platelet-activating factor (PAF) increased in the epidermis of transgenic mice. Collectively, our data demonstrate that WFDC12 may contribute to the exacerbation of AD-like symptoms in DNFB-induced mouse model by enhancing arachidonic acid metabolism and PAF accumulation and that WFDC12 may be a potential therapeutic target for human atopic dermatitis.


Asunto(s)
Dermatitis Atópica , Animales , Ratones , Humanos , Dermatitis Atópica/genética , Factor de Activación Plaquetaria , Ácido Araquidónico , Dinitrofluorobenceno , Piel , Proteínas , Araquidonato 12-Lipooxigenasa/genética
3.
MedComm (2020) ; 4(2): e229, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36891351

RESUMEN

Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.

4.
Signal Transduct Target Ther ; 8(1): 40, 2023 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-36710269

RESUMEN

The intestinal microbiota has been associated with host immunity as well as psoriasis; however, the mechanism of intestinal microbiota regulating psoriasis needs to be demonstrated systematically. Here, we sought to examine its role and mechanism of action in the pathogenesis of psoriasis. We found that the severity of psoriasis-like skin phenotype was accompanied by changes in the composition of the intestinal microbiota. We performed co-housing and fecal microbial transplantation (FMT) experiments using the K14-VEGF transgenic mouse model of psoriasis and demonstrated that the transfer of intestinal microbiota from mice with severe psoriasis-like skin phenotype exacerbated psoriasiform skin inflammation in mice with mild symptoms, including increasing the infiltration and differentiation of Th17, and increased the abundance of Prevotella, while decreasing that of Parabacteroides distasonis, in the colon. These alterations affected fatty acid metabolism, increasing the abundance of oleic and stearic acids. Meanwhile, gentamicin treatment significantly reduced the abundance of Prevotella and alleviated the psoriasis-like symptoms in both K14-VEGF mice and imiquimod (IMQ)-induced psoriasis-like mice. Indeed, administration of oleic and stearic acids exacerbated psoriasis-like symptoms and increased Th17 and monocyte-derived dendritic cell infiltration in the skin lesion areas in vivo, as well as increased the secretion of IL-23 by stimulating DCs in vitro. At last, we found that, treatment of PDE-4 inhibitor alleviated psoriasis-like phenotype of K14-VEGF mice accompanied by the recovery of intestinal microbiota, including the decrease of Prevotella and increase of Parabacteroides distasonis. Overall, our findings reveal that the intestinal microbiota modulates host metabolism and psoriasis-like skin inflammation in mice, suggesting a new target for the clinical diagnosis and treatment of psoriasis.


Asunto(s)
Disbiosis , Psoriasis , Ratones , Animales , Disbiosis/complicaciones , Factor A de Crecimiento Endotelial Vascular/genética , Aminoquinolinas/efectos adversos , Citocinas/genética , Psoriasis/genética , Ratones Transgénicos , Inflamación/patología , Fenotipo , Ácidos Grasos
5.
Crit Rev Microbiol ; 49(1): 82-100, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35603929

RESUMEN

Akkermansia muciniphila, an intestinal microorganism, belongs to Verrucomicrobia, one of the most abundant microorganisms in the mammalian gut. It is a mucin-degrading bacterium that can colonise intestines of mammals such as humans and mice by utilising mucin as the only nitrogen and carbon source. When A. muciniphila colonises the intestine, its metabolites interact with the intestinal barrier, affecting host health by consolidating the intestinal barrier, regulating metabolic functions of the intestinal and circulatory systems, and regulating immune functions. This review summarised the mechanisms of A. muciniphila-host interactions that are relevant to host health. We focussed on characteristics of A. muciniphila in relation to its metabolites to provide a comprehensive understanding of A. muciniphila and its effects on host health and disease processes.


Asunto(s)
Akkermansia , Verrucomicrobia , Humanos , Animales , Ratones , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Akkermansia/metabolismo , Mucinas/metabolismo , Mamíferos/metabolismo
6.
J Autoimmun ; 133: 102916, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36209691

RESUMEN

Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis.


Asunto(s)
Multiómica , Calidad de Vida , Fosfatidilinositol 3-Quinasas , Epigenómica
7.
Front Immunol ; 13: 873720, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36148224

RESUMEN

Whey acidic protein four-disulfide core domain protein 12 (WFDC12) has been implicated in the pathogenesis of psoriasis but the specific molecular mechanism is not clearly defined. In this study, we found the expression of WFDC12 protein closely correlated with psoriasis. WFDC12 in keratinocyte might increase infiltration of Langerhans cells (LCs) and monocyte-derived dendritic cells (moDDCs), up-regulating the co-stimulation molecular CD40/CD86. Th1 cells in lymph nodes were higher in K14-WFDC12 transgenic psoiasis-like mice. Meanwhile, the mRNA of IL-12 and IFN-γ in the lesion skin was significantly increased in transgenic mice. Moreover, we found that the expression of the proteins that participated in the retinoic acid-related pathway and immune signaling pathway was more changed in the lesion skin of K14-WFDC12 transgenic psoriasis-like mice. Collectively, the results implied that WFDC12 might affect the activation of the retinoic acid signaling pathway and regulate the infiltration of DC cells in the skin lesions and lymph nodes, thereby inducing Th1 cells differentiation and increasing the secretion of IFN-γ to exacerbate psoriasis in mice.


Asunto(s)
Psoriasis , Animales , Modelos Animales de Enfermedad , Interleucina-12 , Ratones , Ratones Transgénicos , Proteínas de la Leche , Psoriasis/genética , ARN Mensajero/metabolismo , Tretinoina
8.
Front Immunol ; 13: 877939, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36003378

RESUMEN

Cancer is a major disease endangering human health. More and more studies have shown that microorganisms play an extremely important role in the occurrence, development and treatment of tumors. As a very promising tumor treatment strategy, immunotherapy has also been proved to have a great relationship with microorganisms. Here, the authors review the contribution of the microbiota to cancer and the research on its impact on cancer immunotherapy. We also highlight the possible mechanism of their interaction and outlined the potential application of microbiota in tumor immunotherapy.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Neoplasias , Carcinogénesis , Humanos , Inmunidad , Factores Inmunológicos , Inmunoterapia , Neoplasias/terapia
9.
Cell Death Dis ; 13(7): 635, 2022 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-35864103

RESUMEN

Defective execution of proteases and protease inhibitors that mediate abnormal signaling cascades is emerging as a key contributor to skin diseases, such as psoriasis. SerpinB7 is identified as a skin-specific endogenous protease inhibitor, but the role and underlying mechanism in psoriasis are poorly understood. Here we found that SerpinB7 is highly expressed in psoriatic keratinocytes of patients and imiquimod-induced psoriatic lesions in mice. SerpinB7-/- mice showed abnormal epidermal barrier integrity and skin architecture in homeostasis, and aggravated psoriatic lesion with inhibiting terminal differentiation and increasing inflammatory cells infiltration compared to SerpinB7+/+ mice after Imiquimod treatment. Mechanistically, SerpinB7 deficiency results in excessive proliferation and impaired differentiation, as well as increased chemokines and antimicrobial peptide expression in normal human epidermal keratinocyte and mouse primary keratinocyte. Transcriptomics and proteomics results showed that the SeprinB7 deficiency affected keratinocyte differentiation and proinflammatory cytokines, possibly by affecting the calcium ion channel-related proteins. Notably, we demonstrated that SerpinB7 deficiency prevented the increase in intracellular Ca2+ influx, which was partly eliminated by the intracellular Ca2+ chelator BAPTA-AM. Our findings first described the critical role of SerpinB7 in the regulation of keratinocyte differentiation and psoriatic microenvironment mediated via keratinocytes' intracellular calcium flux, proposing a new candidate for therapeutic targets in psoriasis.


Asunto(s)
Queratinocitos , Psoriasis , Serpinas , Animales , Calcio/metabolismo , Proliferación Celular , Epidermis/metabolismo , Humanos , Imiquimod , Queratinocitos/citología , Ratones , Psoriasis/inducido químicamente , Psoriasis/metabolismo , Serpinas/genética , Serpinas/metabolismo
10.
Signal Transduct Target Ther ; 7(1): 19, 2022 01 20.
Artículo en Inglés | MEDLINE | ID: mdl-35046386

RESUMEN

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.


Asunto(s)
Carcinogénesis/inmunología , Colitis/inmunología , Neoplasias Colorrectales/inmunología , Interleucina-1/inmunología , Proteínas de Neoplasias/inmunología , Receptores de Interleucina-1/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Carcinogénesis/genética , Colitis/genética , Colitis/patología , Neoplasias Colorrectales/genética , Interleucina-1/genética , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Receptores de Interleucina-1/genética
11.
Cardiovasc Res ; 118(9): 2179-2195, 2022 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34375400

RESUMEN

AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.


Asunto(s)
Proteínas de Unión al Calcio , Moléculas de Adhesión Celular , Trampas Extracelulares , Macrófagos , Infarto del Miocardio , Remodelación Ventricular , Animales , Biomarcadores/sangre , Proteínas de Unión al Calcio/sangre , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/deficiencia , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Trampas Extracelulares/genética , Trampas Extracelulares/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/sangre , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Remodelación Ventricular/genética , Remodelación Ventricular/fisiología , Tirosina Quinasa c-Mer/metabolismo
12.
J Colloid Interface Sci ; 606(Pt 2): 1261-1273, 2022 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-34492464

RESUMEN

Constructing a p-n heterojunction is a feasible strategy to manipulate the dynamic behaviors of photogenerated carriers through an internal electric field. Herein, a novel highly efficient indium oxide/bismuth oxyiodide (In2O3/BiOI) p-n junction photocatalyst was fabricated using a facile ionic liquid-assisted precipitation method for the first time. The morphologies were modified by adding different amounts of acetic acid solution. Their hierarchical architecture was beneficial for adsorbing contaminants in wastewater, while the in-situ formed p-n heterojunction between BiOI and In2O3 facilitated interfacial charge transfer and improved the quantum efficiency. Their visible light-responsive photocatalytic activities were systematically investigated by photocatalytic o-phenylphenol (OPP) and 4-tert-butylphenol (PTBP) oxidation. The degradation rate of OPP over In2O3/BiOI-2 was up to 5.67 times higher than that for BiOI. The excellent activity of In2O3/BiOI should be attributed to the rapid interfacial charge transfer, depressed carrier recombination, and proper band potentials. Trapping experiments and electron paramagnetic resonance characterizations confirmed the generation of hydroxyl radicals (•OH) and superoxide radicals (•O2-), which have played a key role in decomposing pollutants. The intermediate products generated during the photocatalytic degradation of OPP were detected and identified by liquid chromatography-mass spectrometry. Meanwhile, their possible molecular structures and degradation pathways have also been inferred.


Asunto(s)
Contaminantes Ambientales , Líquidos Iónicos , Estructuras Metalorgánicas , Bismuto , Catálisis , Indio
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