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1.
Front Immunol ; 15: 1329009, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455045

RESUMO

Objectives: The most frequent cause of kidney damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN), which is also a significant risk factor for morbidity and mortality. Lactate metabolism and protein lactylation might be related to the development of LN. However, there is still a lack of relative research to prove the hypothesis. Hence, this study was conducted to screen the lactate-related biomarkers for LN and analyze the underlying mechanism. Methods: To identify differentially expressed genes (DEGs) in the training set (GSE32591, GSE127797), we conducted a differential expression analysis (LN samples versus normal samples). Then, module genes were mined using WGCNA concerning LN. The overlapping of DEGs, critical module genes, and lactate-related genes (LRGs) was used to create the lactate-related differentially expressed genes (LR-DEGs). By using a machine-learning algorithm, ROC, and expression levels, biomarkers were discovered. We also carried out an immune infiltration study based on biomarkers and GSEA. Results: A sum of 1259 DEGs was obtained between LN and normal groups. Then, 3800 module genes in reference to LN were procured. 19 LR-DEGs were screened out by the intersection of DEGs, key module genes, and LRGs. Moreover, 8 pivotal genes were acquired via two machine-learning algorithms. Subsequently, 3 biomarkers related to lactate metabolism were obtained, including COQ2, COQ4, and NDUFV1. And these three biomarkers were enriched in pathways 'antigen processing and presentation' and 'NOD-like receptor signaling pathway'. We found that Macrophages M0 and T cells regulatory (Tregs) were associated with these three biomarkers as well. Conclusion: Overall, the results indicated that lactate-related biomarkers COQ2, COQ4, and NDUFV1 were associated with LN, which laid a theoretical foundation for the diagnosis and treatment of LN.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Ácido Láctico , Biomarcadores , Transdução de Sinais
2.
Clin Immunol ; 256: 109778, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37730009

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested a potential role of ferroptosis, an iron-dependent form of regulated cell death, in the pathogenesis of SLE. Here, we demonstrate that B-cell ferroptosis occurs both in lupus patients and MRL/lpr mice. Treatment with liproxstatin-1, a potent ferroptosis inhibitor, could reduce autoantibody production, improve renal damage, and alleviate lupus symptoms in vivo. Furthermore, our results suggest that ferroptosis may regulate B cell differentiation and plasma cell formation, indicating a potential mechanism for its involvement in SLE. Taken together, targeting ferroptosis in B cells may be a promising therapeutic strategy for SLE.


Assuntos
Ferroptose , Lúpus Eritematoso Sistêmico , Humanos , Camundongos , Animais , Camundongos Endogâmicos MRL lpr , Linfócitos B , Rim/patologia
3.
Epigenetics ; 18(1): 2226492, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37343193

RESUMO

Increasing evidence has uncovered the essential roles of long noncoding RNAs (lncRNAs) in biological and pathological functions of dendritic cells (DCs) among patients with systemic lupus erythematosus (SLE). However, whether lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) could modulate DCs, especially in the inflammation of SLE, remains largely unknown. Fifteen SLE patients and fifteen age-matched healthy controls were included, and their monocyte-derived dendritic cells (moDCs) were cultured in vitro. Our research identified that the expression of NEAT1 was significantly increased in moDCs of SLE patients and positively correlated with disease activity. Interleukin 6 (IL-6) from both plasma and secreted supernatants of moDCs was also elevated in the SLE group. In addition, regulation of NEAT1 in moDCs by transfection could lead to the corresponding change in IL-6 generation. While for miR-365a-3p, a micro-RNA that can bind with the 3' UTR region of IL6 and NEAT1, it may serve as a negative modulator since its overexpression could result in the reduction of IL-6 levels and vice versa. Additionally, the elevation in NEAT1 expression could increase the secretion of IL-6 by specifically binding to miR-365a-3p, reducing the negative modulatory effects of miR-365a-3p on the IL6 target gene, which suggested that elevated NEAT1 expression could function as the competing endogenous RNA (ceRNA). In conclusion, our findings indicate that NEAT1 can efficiently sponge miR-365a-3p to upregulate expression and secretion of IL-6 in moDCs, suggesting that the NEAT1/miR-365a-3p/IL6 axis may be involved in the development of SLE disease.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , RNA Longo não Codificante , Humanos , Células Dendríticas/metabolismo , Metilação de DNA , Interleucina-6/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Monócitos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
4.
Front Immunol ; 13: 977394, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211414

RESUMO

Immune-mediated inflammatory diseases(IMIDs) are referred to as highly disabling chronic diseases affecting different organs and systems. Inappropriate or excessive immune responses with chronic inflammation are typical manifestations. Usually in patients with chronic infection and cancer, due to long-term exposure to persistent antigens and inflammation microenvironment, T-cells are continuously stimulated and gradually differentiate into an exhausted state. Exhausted T-cells gradually lose effector function and characteristics of memory T-cells. However, existing studies have found that exhausted T-cells are not only present in the infection and tumor environment, but also in autoimmunity, and are associated with better prognosis of IMIDs. This suggests new prospects for the application of this reversible process of T-cell exhaustion in the treatment of IMID. This review will focus on the research progress of T-cell exhaustion in several IMIDs and its potential application for diagnosis and treatment in IMIDs.


Assuntos
Imunoterapia , Neoplasias , Autoimunidade , Humanos , Fatores Imunológicos , Inflamação , Neoplasias/terapia , Microambiente Tumoral
5.
Front Immunol ; 13: 985729, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36741410

RESUMO

Objectives: Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. Methods: The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. Results: The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factor-alpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). Conclusion: This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream.


Assuntos
Citocinas , Lúpus Eritematoso Sistêmico , Humanos , Citocinas/genética , Interleucina-17/genética , Interleucina-6/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Causalidade , Interferon gama/genética , Lúpus Eritematoso Sistêmico/genética
6.
Thromb J ; 19(1): 27, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910580

RESUMO

BACKGROUND: Sphingomyelin (SM) is an essential component of biological lipid rafts, and it plays an indispensable role in maintaining plasma membrane stability and in mediating signal transduction. The ultimate biosynthesis of SM is catalyzed by two sphingomyelin synthases (SMSs) namely SMS1 and SMS2, which are selectively distributed in the trans-Golgi apparatus and the plasma membrane. It has been demonstrated that SMS2 acts as an irreplaceable molecule in the regulation of transmembrane signaling, and loss of SMS2 has been reported to worsen atherosclerosis and liver steatosis. However, the function of SMS2 in platelet activation and its association with the pathological process of thrombosis in acute coronary syndrome (ACS) and portal hypertension (PH) remain unclear. METHODS: In this study, we tested the role of SMS2 in platelet activation and thrombosis using SMS2 knockout (SMS2 -/-) mice and SMS2-specific inhibitor, D609. Furthermore, we detected SMS2 expression in patients with ACS and PH. RESULTS: SMS2 -/- platelets showed significant reduction in platelet aggregation, spreading, clot retraction and in vivo thrombosis. Similar inhibitory effects on platelet activation were detected in D609-treated wild-type platelets. PLCγ/PI3K/Akt signaling pathway was inhibited in SMS2 -/- platelets and D609-treated wild-type platelets. In addition, we discovered that platelet SMS2 expression was remarkably increased in patients with ACS and PH, compared with healthy subjects. CONCLUSIONS: Our study indicates that SMS2 acts as a positive regulator of platelet activation and thrombosis, and provides a theoretical basis for the potential use of D609 in anti-thrombosis treatment.

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