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Purpose: Neuroinflammation is a characteristic feature of neurodegenerative diseases. Mesenchymal stem cell-derived exosomes (MSC-exo) have shown neuroprotective effects through immunoregulation, but the therapeutic efficacy remains unsatisfactory. This study aims to enhance the neuroprotective capacity of MSC-exo through IL-23 priming for treating retinal degeneration in mice. Methods: MSC were primed with IL-23 stimulation in vitro, and subsequently, exosomes (MSC-exo and IL-23-MSC-exo) were isolated and characterized. Two retinal degenerative disease models (NaIO3-induced mice and rd10 mice) received intravitreal injections of these exosomes. The efficacy of exosomes was assessed by examining retinal structural and functional recovery. Furthermore, exosomal microRNA (miRNA) sequencing was conducted, and the effects of exosomes on the M1 and M2 microglial phenotype shift were evaluated. Results: IL-23-primed MSC-derived exosomes (IL-23-MSC-exo) exhibited enhanced capability in protecting photoreceptor cells and retinal pigment epithelium (RPE) cells against degenerative damage and fostering the restoration of retinal neural function in both NaIO3-induced retinal degeneration mice and rd10 mice when compared with MSC-exo. The exosomal miRNA suppression via Drosha knockdown in IL-23-primed MSC would abolish the neuroprotective role of IL-23-MSC-exo, highlighting the miRNA-dependent mechanism. Bioinformatic analysis, along with further in vivo biological studies, revealed that IL-23 priming induced a set of anti-inflammatory miRNAs in MSC-exo, prompting the transition of M1 to M2 microglial polarization. Conclusions: IL-23 priming presents as a potential avenue for amplifying the immunomodulatory and neuroprotective effects of MSC-exo in treating retinal degeneration.
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Modelos Animais de Doenças , Exossomos , Interleucina-23 , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Degeneração Retiniana , Animais , Exossomos/metabolismo , Exossomos/transplante , Degeneração Retiniana/terapia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/prevenção & controle , Camundongos , Células-Tronco Mesenquimais/metabolismo , Interleucina-23/metabolismo , MicroRNAs/genética , Injeções Intravítreas , Fármacos Neuroprotetores , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Iodatos/toxicidade , Células Cultivadas , Microglia/metabolismo , MasculinoRESUMO
The microglia-mediated neuroinflammation have been shown to play a crucial role in the ocular pathological angiogenesis process, but specific immunotherapies for neovascular ocular diseases are still lacking. This study proposed that targeting GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) might be a novel immunotherapy for these angiogenesis diseases. We found a significant upregulation of CGAS and STING genes in the RNA-seq data derived from retinal tissues of the patients with proliferative diabetic retinopathy. In experimental models of ocular angiogenesis including laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), the cGAS-STING pathway was activated as angiogenesis progressed. Either genetic deletion or pharmacological inhibition of STING resulted in a remarkable suppression of neovascularization in both models. Furthermore, cGAS-STING signaling was specifically activated in myeloid cells, triggering the subsequent RIP1-RIP3-MLKL pathway activation and leading to necroptosis-mediated inflammation. Notably, targeted inhibition of the cGAS-STING pathway with C-176 or SN-011 could significantly suppress pathological angiogenesis in CNV and OIR. Additionally, the combination of C-176 or SN-011 with anti-VEGF therapy led to least angiogenesis, markedly enhancing the anti-angiogenic effectiveness. Together, our findings provide compelling evidence for the importance of the cGAS-STING-necroptosis axis in pathological angiogenesis, highlighting its potential as a promising immunotherapeutic target for treating neovascular ocular diseases.
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Proteínas de Membrana , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Nucleotidiltransferases , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/antagonistas & inibidores , Animais , Humanos , Camundongos , Doenças Neuroinflamatórias/metabolismo , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Neovascularização de Coroide/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Camundongos Knockout , Retinopatia Diabética/metabolismoRESUMO
BACKGROUND: There is growing evidence indicating immune inflammation is a key factor in the progression of chronic obstructive pulmonary disease (COPD). Immune checkpoints (ICs) are crucial targets for modulating the functional activation and differentiation of immune cells, particularly in relation to immune inflammation and the regulation of T cell activation and exhaustion. However, the precise mechanisms of ICs in COPD remain understood. METHODS: COPD datasets were obtained from the Gene Expression Omnibus (GEO) and analyzed using GEO2R and Limma to identify differentially expressed genes. LASSO regression was then applied to screen ICs closely associated with COPD. Finally, target genes were selected based on gene expression profiles. Gene ontology (GO), immune infiltration analysis, and gene set enrichment analysis (GSEA) were utilized to assess the relationship between IC genes (ICGs) and immune cells. Subsequently, tobacco-exposed mice, anti-Tim3-treated mice, and HAVCR2-knockout mice were generated, with flow cytometry being used to confirm the results. RESULTS: Through the analysis of GSE38974 and LASSO regression, five ICGs were identified. Subsequent validation using GSE20257 and GSE76925 confirmed these findings. Gene expression profiling highlighted HAVCR2 as having the strongest correlation with COPD. Further investigation through immune infiltration analysis, GO, and GSEA indicated a link between HAVCR2 and CD8+ T cells in COPD. Flow cytometry experiments demonstrated high Tim3 expression in CD8+ T cells of mice exposed to tobacco, promoting Tc1 and inhibiting Tc17, thus affecting CD8+ Tem activation and CD8+ Tcm formation, leading to an immune imbalance within CD8+ T cells. CONCLUSION: Prolonged exposure to tobacco upregulates Tim3 in CD8+ T cells, triggering its regulatory effects on Tc1/Tc17. Knocking out HAVCR2 further upregulated the expression of CD8+ Tem while suppressing the expression of CD8+ Tcm, indicating that Tim3 plays a role in the activation and differentiation of CD8+ T cells in the context of tobacco exposure.
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Biologia Computacional , Receptor Celular 2 do Vírus da Hepatite A , Doença Pulmonar Obstrutiva Crônica , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Animais , Humanos , Camundongos , Biologia Computacional/métodos , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Perfilação da Expressão Gênica/métodos , Camundongos Knockout , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos Endogâmicos C57BL , MasculinoRESUMO
TIGIT, a co-inhibitory receptor found on T cells and NK cells, transmits inhibitory signals upon binding to its ligand. This interaction suppresses the activation of various signaling pathways, leading to functional exhaustion of cells, ultimately dampening excessive inflammatory responses or facilitating immune evasion in tumors. Dysregulated TIGIT expression has been noted in T cells across different inflammatory conditions, exhibiting varying effects based on T cell subsets. TIGIT predominantly restrains the effector function of pro-inflammatory T cells, upholds the suppressive function of regulatory T cells, and influences Tfh maturation. Mechanistically, the IL27-induced transcription factors c-Maf and Blimp-1 are believed to be key regulators of TIGIT expression in T cells. Notably, TIGIT expression in T cells is implicated in lung diseases, particularly airway inflammatory conditions such as lung cancer, obstructive pulmonary disease, interstitial lung disease, sarcoidosis, and COVID-19. This review emphasizes the significance of TIGIT in the context of T cell immunity and airway inflammatory diseases.
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Hypoxia-induced retinal neovascularization is a leading cause of blindness worldwide. Oxygen-induced retinopathy (OIR) mouse, a well-established angiogenesis model, has been extensively used to evaluate the effect of anti-angiogenic agents through intravitreal injection. Here, we serendipitously found that the needles used for intravitreal injection caused an unexpected "anti-angiogenic" effect in the OIR mice. To evaluate the effects of various intravitreal puncture sizes on retinal neovascularization and explore the potential underlying mechanism, intravitreal punctures using 0.5 mm (25 G), 0.3 mm (30 G), or 0.21 mm (33 G) needles were performed in OIR mice. Compared with 0.3 mm and 0.21 mm puncture, the 0.5 mm puncture remarkably suppressed the formation of pathological angiogenesis, inhibited vascular leakage, and remodeled the retinal vasculature. Mechanistically, the 0.5 mm puncture induced a substantial reduction in intraocular pressure (IOP), leading to an improvement in oxygen partial pressure (pO2) and significant reduction in Hif1a expression, resulting in resolution of angiogenic and inflammatory responses. Furthermore, IOP-lowering drugs, Travatan or Azarga, also promoted the alleviation of hypoxia and exhibited a potent anti-angiogenesis efficacy. Our study revealed an acute and significant reduction in IOP caused by a large puncture, which could remarkably suppress HIF-1α-mediated retinal neovascularization, indicating that lowering IOP may be a promising therapeutic avenue for treating retinal neovascular diseases.
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Doenças Retinianas , Neovascularização Retiniana , Animais , Camundongos , Neovascularização Retiniana/metabolismo , Pressão Intraocular , Neovascularização Patológica/tratamento farmacológico , Oxigênio/uso terapêutico , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Camundongos Endogâmicos C57BLRESUMO
Introduction: Though the important effect of cultural identity on subjective well-being is widely acknowledged, the details of how different cultures' unique features influence well-being remain to be revealed. To address this issue in the context of Chinese culture, the present study investigates whether and how the prominent features of Chinese culture-collectivism and red culture-shape Chinese people's subjective well-being. Methods: The Red Cultural Identity Scale, Subjective Well-Being Scale, Collectivism Scale, and Perspective-Taking Scale were used to assess 1,045 Chinese residents. Results: The results showed that red cultural identity positively predicted participants' subjective well-being through the mediated role of collectivism. Furthermore, perspective-taking was found to moderate the mediating effect of collectivism. Discussion: These results demonstrate that the way cultural identity predicts subjective well-being is highly correlated to specific cultural features, e.g., the opinion of values, which was significant in practice with a cross-cultural background.