IL6/adiponectin/HMGB1 feedback loop mediates adipocyte and macrophage crosstalk and M2 polarization after myocardial infarction.

Background: Differences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone. Methods: The LVA, MI, and SHAM mouse models were used. Echocardiography, Masson's trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN. Results: A novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment. Conclusion: The IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

[Amplification of immune cells derived from human peripheral blood and cytotoxicity on MDA-MB-231 breast cancer cells in vitro].

Objective To investigate the cytotoxicity of cytokine induced killer (CIK) and natural killer (NK) cells derived from human peripheral blood on MDA-MB-231 breast cancer in vitro. Methods The MDA-MB-231 human breast cancer cells were infected with lentivirus containing red fluorescent protein (RFP) and luciferase (Luc) genes. The expression of RFP and Luc genes were detected by florescence microscopy. Peripheral blood mononuclear cells (PBMCs) were isolated from the patients to induce the information of dendritic cells (DCs), CIK and NK cells. Then DCs and CIK cells were co-cultured to induce the formation of DC-CIK cells. The amplification effect and the immunophenotypes of immune cells were detected by flow cytometry. And then the cytotoxicity of immune cells DC-CIK, CIK and NK cells on MDA-MB-231 breast cancer cells were analyzed at different effector-target ratios. Results he effects of DC-CIK, NK and CIK cells on MDA-MB-231 tumor cells increased with the increase of effector-target ratio and the extension of action time. After co-culture of 72 hours, the killing rate of immune cells on target cells reached more than 90%. Conclusion CIK, DC-CIK and NK cells amplified in vitro have apoptosis effects on breast cancer cells.