The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response.
Background/Aims: To clarify the effect of fluoride on splenic B cells, the endocytosis and surface marker expression levels of mouse splenic B cells were detected in vitro by flow cytometry. Methods: Cells were stimulated with 10 µg/mL lipopolysaccharide (LPS) and varying concentrations of Sodium Fluoride (NaF) (0, 50 µM, 100 µM, 500 µM, 1000 µM). Results: The results demonstrated that the endocytic capacity of B cells was enhanced by NaF at 50µM. NaF significantly enhanced CD80 expression at 50 µM and decreased CD86 expression at 500 µM. CD40 and CD138 expression on B cells were down-regulated at varying high concentrations of NaF. Conclusion: our results showed that the endocytic capacity, expression levels of CD40 and CD80 of B cells changed significantly at lower concentrations, whereas expression levels of CD138 and CD86 changed significantly at higher concentrations, suggesting that fluoride could inhibit immune function in animals.
Objectives: Osteosarcoma (OS) is the most common primary solid malignant tumor of the bone in adolescents. Conventional treatment of OS by surgery and chemotherapy is not effective and the prognosis is poor. Our previous study demonstrated that a novel cell-penetrating peptide (KRP) that, coupled to doxorubicin (DOX), allowed specific tumor targeting. However, the underlying molecular mechanisms of the KRP-DOX antitumor effect were not completely elucidated. Therefore, the present work aimed to identify key candidate genes by integrated bioinformatics analysis. Methods: Differentially expressed genes (DEGs) were screened using the Network Analyst. The functions and pathway involvements of the DEGs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, respectively. The protein-protein interaction (PPI) network was used to identify hub genes. In addition, quantitative RT-PCR (qRT-PCR) and Western blotting were performed to assess the expression level of candidate biomarkers in OS cells after KRP-DOX treatment. Results: A total of 790 DEGs were identified. GO functional analysis and KEGG pathway analysis demonstrated that the DEGs were mostly enriched in the ribosome. DEGs were visualized by PPI networks. After treatment of OS cells with KRP-DOX, the downregulated ribosomal protein S6 kinase A2 (RPS6KA2) was found to be closely related to inhibition of OS proliferation. In agreement with the bioinformatics analysis, qRT-PCR and western blot results showed low expression of RPS6KA2 in osteosarcoma cells in the KRP-DOX treatment group.Conclusions: RPS6KA2 is significantly associated with the KRP-DOX anti-tumor effect and may serve as a candidate biomarker and therapeutic target for OS.
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