The PD-1 with PD-L1 Axis Is Pertinent with the Immune Modulation of Atrial Fibrillation by Regulating T Cell Excitation and Promoting the Secretion of Inflammatory Factors

Abstract

Objective. To analyze the role of PD-1/PD-L1 signaling pathway in regulating T cell activation and secretion of proinflammatory factors in atrial fibrillation. Methods. Forty-five patients with atrial fibrillation admitted to the cardiology department of our hospital from July 2019 to March 2021 were selected to be included in the atrial fibrillation group, and another 45 healthy volunteers were selected as the control group to compare the changes of T cell CD69 and human leukocyte antigen-DR (HLA-DR) expression in the peripheral blood of the two study groups; compare the changes of programmed death factor-1 on CD4+ and CD8+ lymphocytes in the peripheral blood of the two groups (PD-1) expression changes and PD-L1 and PD-L2 expression changes on peripheral blood myeloid dendritic cells (mDCs) cells; compare the changes of interleukin-2, interleukin-6, interleukin-10, and interleukin-17A (IL-2, IL-6, IL-10, and IL-17), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) concentrations on peripheral blood inflammatory factors in the two groups; and isolate the two groups of peripheral blood mDCs cells; α interferon upregulated PD-L1 expression in the cells and analyzed the effect of PD-L1 expression on the ability of mDCs to stimulate T cells to secrete cytokines.Results. The positive expression rates of CD69 and HLA-DR on peripheral blood CD3+ T lymphocytes were significantly higher in patients in the atrial fibrillation group than in the control group, and the differences were statistically significant ( P < 0.01 ). The positive expression rate of PD-1 on CD4+ lymphocytes was significantly lower in patients in the atrial fibrillation group than in the control group ( P < 0.01 ). There was no statistically significant difference between the two groups in terms of PD-1 positive expression rate on CD8+ lymphocytes ( P > 0.05 ). The positive expression rate of PD-L1 on mDCs cells was significantly lower in patients in the atrial fibrillation group than in the control group ( P < 0.01 ), and there was no statistically significant difference between the two groups in the positive expression rate of PD-L2 on mDCs cells, PD-L1, and PD-L2 on CD4+ and CD8+ T cells ( P > 0.05 ). The concentrations of IL-2, IL-6, IL-10, and IFN-γ in peripheral blood were significantly higher in patients in the atrial fibrillation group than in the control group ( P < 0.05 ), and there was no statistically significant difference in the comparison of IL-17A and TNF concentrations in peripheral blood between the two groups ( P > 0.05 ). In the atrial fibrillation group, the ability of mDCs to stimulate T cells to secrete IL-2 and IFN-γ was significantly higher, and the ability to secrete IL-10 was significantly lower compared with the control group ( P < 0.05 ). After α interferon upregulated PD-L1 expression in cells, the ability of mDCs to stimulate T cells to secrete IL-2, IL-10, and IFN-γ cytokines was reversed in patients in the atrial fibrillation group, and the differences compared with the control group were not statistically significant ( P > 0.05 ). Conclusion. PD-1/PD-L1 signaling pathway may play an immunomodulatory role in the pathogenesis of atrial fibrillation by promoting increased secretion of inflammatory factors through regulating T cell activation.

Fish Oil Ameliorates Vibrio parahaemolyticus Infection in Mice by Restoring Colonic Microbiota, Metabolic Profiles, and Immune Homeostasis

“…51 Many pathogen-induced immunopathological and inflammatory diseases are related to CD 3+ T cell-mediated disorders with an abundance of CD 3+ T cells activating the TLR4 pathway, resulting in the promotion of inflammatory factors like IL-6, IL-17, and TNF-α, which infiltrate the surrounding tissue. 52 Our results showed that acute Vp infection caused increased CD 3+ T cells, overexpression of Tlr2, Tlr4, MyD88, and Nf-κb genes, and increased colonic inflammatory cytokine IL-17 and TNF-α levels. In contrast, FO presupplementation markedly reduced Vp-induced accumulation of CD 3+ T cells in the colonic tissue, alleviated excessive inflammation, and boosted the IFN-γ and IL-4 levels, which are important for the regulation of gut immunological homeostasis.…”

“…The homeostasis of intestinal immunity is essential for the integrity of the intestine so that it can recover easily from exposure to gastrointestinal infections. , In this regard, the intestinal epithelial cells, innate immune cells like macrophages, mast cells, and DCs, and in particular adaptive immune cells like T cells (CD 3+ , CD 4+ , and CD 8+ ) play a key role in the recovery from bacterial, fungal, and viral infections . Many pathogen-induced immunopathological and inflammatory diseases are related to CD 3+ T cell-mediated disorders with an abundance of CD 3+ T cells activating the TLR4 pathway, resulting in the promotion of inflammatory factors like IL-6, IL-17, and TNF-α, which infiltrate the surrounding tissue . Our results showed that acute Vp infection caused increased CD 3+ T cells, overexpression of Tlr2 , Tlr4 , MyD88 , and Nf-κb genes, and increased colonic inflammatory cytokine IL-17 and TNF-α levels.…”

“…53,70 Escherichia, Vibrios, and Prevotella were positively correlated with IL-17, TNF-α, colonic histidine, isolithocholic acid, and deoxycholic acid, indicating that these opportunistic pathogenic bacteria promote inflammation and accumulation of harmful metabolites. 52,66 Many studies have shown that cytokines IL-17 and TNF-α are involved in the TLR4 pathway-mediated inflammation, while Roseburia and Akkermansia species can inhibit the action of the TLR4 pathway by producing SCFAs to suppress LPS binding to TLR4 receptor on the epithelial cell surface and downregulation of Tlr4/Tlr2 genes. 75−77 Consistently, our results suggested that a 4 mg FO dose upregulated the abundance of Roseburia and Akkermansia and their derived propionic acid and butyric acid levels to downregulate the gene expression of In summary, pretreatment with 4 mg of FO minimized intestinal pathological damage, strengthened the mucosal barrier, and sustained epithelial permeability in Vp-infected mice.…”

“…Indeed, n -3 PUFAs could directly influence the gut microbiota composition by increasing the abundance of genera with a potential beneficial effect, which promote the accumulation of beneficial metabolites in the gut and thereby positively regulate immune cell activation and trigger an immune cascade , Escherichia , Vibrios , and Prevotella were positively correlated with IL-17, TNF-α, colonic histidine, isolithocholic acid, and deoxycholic acid, indicating that these opportunistic pathogenic bacteria promote inflammation and accumulation of harmful metabolites. , Many studies have shown that cytokines IL-17 and TNF-α are involved in the TLR4 pathway-mediated inflammation, while Roseburia and Akkermansia species can inhibit the action of the TLR4 pathway by producing SCFAs to suppress LPS binding to TLR4 receptor on the epithelial cell surface and downregulation of Tlr4 / Tlr2 genes. − Consistently, our results suggested that a 4 mg FO dose upregulated the abundance of Roseburia and Akkermansia and their derived propionic acid and butyric acid levels to downregulate the gene expression of Tlr2 , Tlr4 , and Nf-κb and thereby minimize Vp-induced proinflammatory factor IL-17 and TNF-α production. Future studies are required to explore the mechanistic link between the intestinal gene expression, microbial community, and secretion of associated metabolites during the alleviation of Vp infection by FO.…”

Screening of atrial fibrillation diagnostic markers based on a GEO database chip and bioinformatics analysis

“…In addition, the programmed cell death 1 (PD-1) and programmed cell death-Ligand 1 (PD-L1) pathways may play immunomodulatory roles in the pathogenesis of AF by regulating T cell excitation and thus promoting cytokine excretion ( 39 ). The above-mentioned findings suggest that the helper T cell population and its cytokines are closely associated with the progression of AF.…”