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Neuropilin‐2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in colitis remains unclear. Here, we found that NRP2 was an inflammation‐sensing protein rapidly and dramatically induced in myeloid cells, especially in macrophages, under inflammatory contexts. NRP2 deficiency in myeloid cells exacerbated dextran sulfate sodium salt‐induced experimental colitis by promoting polarization of M1 macrophages and colon injury. Mechanistically, NRP2 could be induced via NF‐κB activation by TNF‐α in macrophages, but exerted an inhibitory effect on NF‐κB signaling, forming a negative feedback loop with NF‐κB to sense and alleviate inflammation. Deletion of NRP2 in macrophages broke this negative feedback circuit, leading to NF‐κB overactivation, inflammatory exacerbation, and more severe colitis. Collectively, these findings reveal inflammation restriction as a role for NRP2 in macrophages under inflammation contexts and suggest that NRP2 in macrophages may relieve inflammation in inflammatory bowel disease. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription 5 (Stat5) is known to engage in regulating the differentiation and effector function of various subsets of T helper cells. However, how Stat5 regulates the antitumor activity of tumor-infiltrating CD4+ T cells is largely unknown. Here, we showed that mice with specific deletion of Stat5 in CD4+ T cells were less susceptible to developing subcutaneous and lung metastatic B16 melanoma with CD4+ tumor-infiltrating lymphocytes (TILs) remolding. Especially, we confirmed that Stat5-deficient CD4+ naïve T cells were prone to polarization of two subtypes of Th17 cells: IFN-γ+ and IFN-γ− Th17 cells, which exhibited increased anti-melanoma activity through enhanced activation of Notch1 pathway compared with wild type Th17 cells. Our study therefore revealed a novel function of Stat5 in regulating tumor-specific Th17 cell differentiation and function in melanoma. This study also provided a new possibility for targeting Stat5 and other Th17-associated pathways to develop novel immunotherapies for melanoma patients. [ABSTRACT FROM AUTHOR]

Apelin acts as a tumor promoter in multiple malignant tumors; however, its regulatory mechanism remains unclear. Previous studies have indicated that exosomes are pivotal to mediating tumor progression and metastasis. This study examined whether apelin enhances proliferation and invasion ability of lung cancer cells via exosomal microRNA (miRNA). Lung cancer A549 cells overexpressing apelin and control vector were generated by lentiviral transfection. Exosomes were isolated from the culture supernatant of each cell group and characterized. A-exo and V-exo were, respectively, cocultured with A549 cells, and assays of proliferation, apoptosis, colony formation and invasion were conducted. Exosomal miRNA sequencing (miRNA-seq) was performed on A-exo and V-exo to select a candidate miRNA. It was found that A549 cells absorbed more A-exo than V-exo, and A-exo could promote proliferation, colony formation, migration and invasion of A549 cells more than V-exo. Exosomal miRNA-seq data revealed that miR-15a-5p was markedly lower in A-exo compared with V-exo. Low expression of miR-15a-5p was also found in lung cancer tissues and cell lines, suggesting that miR-15a-5p may have an anti-tumor role. Overexpression of miR-15a-5p in A549 cells was associated with less cell proliferation, migration, invasion and suppressed cell cycle, and lower amounts of CDCA4 (cell division cycle-associated protein 4) indicated that it may be a potential target for miR-15a-5p. This study elucidated a novel regulatory mechanism that apelin may promote proliferation and invasion of lung cancer cells by inhibiting miR-15a-5p encapsulated in exosomes. [ABSTRACT FROM AUTHOR]

Objective: YKL-40, also known as chitinase-3-like-1 (CHI3L1), is a human cartilage glycoprotein-39, with its N-terminus consisting of tyrosine (Y), lysine (K), and leucine (L), hence the name YKL-40. In this study, we explored whether YKL-40 could promote the expression of inflammatory factors in type Ⅱ alveolar epithelial cells., Methods: A549 cells were cultured in vitro with interleukin (IL)-1β (20 ng/mL), IL-6 (20 ng/mL), tumor necrosis factor-alpha (TNF-α) (20 ng/mL), and interferon-gamma (IFN-γ) (20 ng/mL). The expression of YKL -40 transcription was determined by RT-qPCR. A549 cells were cultured with IL-1β at 5, 10, and 20 ng/mL and the expression of YKL-40 protein was determined by Western blot. A549 cells were cultured with recombinant YKL-40 protein at 0, 100, 500, and 1 000 ng/mL and the expression levels of IL-6 and IL-8 were measured by RT-qPCR. Three pairs of small interfering RNAs targeting YKL-40 (si- YKL -40-1/2/3) and the negative control (NC) were designed and used to transfect A549 cells, respectively, and the expression of YKL-40 was determined by RT-qPCR and Western blot. si- YKL -40-3 was screened out for subsequent experiments. In A549 cells, si- YKL -40-3 and si-NC were transfected and, then, IL-1β (20 ng/mL) was added in for culturing. The expression of YKL -40, IL -6, and IL- 8 was determined by RT-qPCR and the expression of multiple factors in the supernatant was measured with the QAH-INF-1 kit., Results: RT-qPCR results showed that IL-1β could up-regulate YKL-40 protein transcription level compared with that of the control group and the difference was statistically significant ( P <0.01), but IL-6, TNF-α, and IFN-γ could not up-regulate YKL-40 protein transcription level. Western blot results showed that IL-1β (20 ng/mL) could significantly promote the expression of YKL-40 and, compared with that of the control group, the differences showed by groups treated with different concentrations of IL-1β were all statistical significant ( P <0.01). After adding human recombinant YKL-40 protein to A549 cells, the results showed that the expression of inflammatory factors IL-6 and IL-8 was significantly increased and the difference was statistically significant compared with that of the control group ( P <0.05). After the expression of YKL-40 was decreased by si- YKL -40-3 transfection, the expression of IL-6 ( P <0.05), IL-8 ( P <0.05), and other inflammatory factors was inhibited compared with that of the control group., Conclusion: YKL-40 can promote the expression and secretion of IL-6, IL-8, and other acute inflammatory factors in A549 cell line, a type Ⅱ alveolar epithelial cell model, thus aggravating the inflammatory response. Targeted inhibition of YKL-40 expression may effectively inhibit inflammatory response., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)