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Background: Interferon regulatory factor 4 (IRF4) is a crucial member of the IRF family of transcription factors and is pivotal in orchestrating the body's defense against tumors and infections by modulating the differentiation and functionality of immune cells. The role of IRF4 in mice during Schistosoma japonicum infection, as well as the effects of IRF4 deficiency on myeloid-derived suppressor cells (MDSCs), remains inadequately understood. Methods: Hematoxylin and eosin staining was used to evaluate the pathological damage in different organs of mice following infection with S. japonicum. Flow cytometry was employed to study the effect of IRF4 on the proliferation and function of myeloid-derived suppressor cells (MDSCs) in S. japonicum-infected mice. Results: Knockout of IRF4 in myeloid cells significantly mitigated pathological damage to the liver and lungs in mice infected with S. japonicum. Knockout of IRF4 in myeloid cells also inhibited the expansion and functionality of MDSCs by downregulating programmed death ligand 2 (PD-L2) expression and interleukin-1 alpha (IL-1α) secretion in mice infected with S. japonicum. Mechanistic studies revealed that IRF4 deficiency inhibited the expansion and function of MDSCs and that this inhibition was mediated by the STAT3 and AKT signaling pathways. Also, IRF4 myeloid knockout promoted the expansion of T cells in S. japonicum-infected mice, but had no significant effect on B cell aggregation. Conclusions: Overall, these findings highlight the importance of IRF4 in regulating MDSCs and their impact on tissue damage during S. japonicum infection, providing valuable insights into potential therapeutic targets for managing the pathological consequences of this parasitic infection. [ABSTRACT FROM AUTHOR]

Naringenin is a citrus flavonoid that potently improves metabolic parameters in animal models of metabolic disorders, such as type 2 diabetes. Estrogen receptor (ER) activation promotes β cell function and survival, thereby improving systemic glucose metabolism. In this study, we used a luciferase reporter assay, isolated rat islets and a diabetic rat model to investigate the effects of naringenin on ER signaling and the underlying mechanism of naringenin-mediated improvement of islet function in diabetes. Naringenin specifically activated ERβ without affecting the activity of ERα, G protein-coupled estrogen receptor (GPER) or estrogen-related receptor (ERR) α/β/γ. Additionally, treatment with naringenin enhanced glucose-stimulated insulin secretion in isolated rat islets. This effect was abrogated by PHTPP, an ERβ antagonist. Transcriptomic analysis revealed that naringenin upregulated the expression of genes, such as Pdx1 and Mafa , which are closely linked to improved β-cell function. In consistence, single administration of naringenin to normal rats elevated plasma insulin levels and improved glucose responses. These beneficial effects were blocked by PHTPP. In streptozocin-nicotinamide induced diabetic rats, treatment for 2 weeks with naringenin alone, but not in combination with PHTPP, significantly restored pancreatic β cell mass and improved glucose metabolism. Collectively, these data support that naringenin specifically activate ERβ to improve insulin secretion in the primary rat islets. Furthermore, naringenin administration also protected β cell function and reversed glucose dysregulation in diabetic rats. These beneficial effects are at least partially dependent on the ERβ pathway. [ABSTRACT FROM AUTHOR]

Malaria remains a significant global public health problem. T follicular helper (Tfh) cells, a subset of CD4+ T cells, have the capacity to regulate B cells, plasma cells, and antibody production, among other functions. Myeloid‐derived suppressor cells (MDSCs) possess strong immunosuppressive abilities and can negatively regulate various immune responses. However, the role of MDSCs in inhibiting Tfh‐cell responses during Plasmodium infection remains unclear. In this study, we investigated the regulatory effect of MDSCs on Tfh cell‐mediated immune responses upon Plasmodium infection. We found that the numbers of MDSCs increased upon Plasmodium infection. Further mechanism study revealed that MDSC‐derived Arg‐1 and PD‐L1 prevented Tfh cell proliferation and activation. Conversely, the addition of nor‐NOHA or anti‐PD‐L1 monoclonal antibodies enhanced the proliferation and activation of Tfh cells, indicating that the inhibitory effect of MDSCs on Tfh cells was dependent on Arg‐1 and PD‐1/PD‐L1. In vivo depletion of MDSCs enhanced Tfh‐cell responses and antibody production, as well as relieved symptoms of infected mice and improved their survival rates. These findings provide insights into the immunosuppressive role of MDSCs in inhibiting Tfh cell immune responses and further impairing humoral immunity. Our study provides new strategies for malaria prevention and control. [ABSTRACT FROM AUTHOR]