miR-21 is aberrantly expressed, and plays a role in various types of tumors and many other diseases. However, the mechanism of miR-21 in LPS-induced septic shock is still unclear. In this study, we investigated the mechanism of miR-21 in LPS-induced pyroptosis and septic shock. Here, we show that miR-21 deficiency inhibited NLRP3, ASC, and caspase-1 expression, as well as inflammasome activation in myeloid cells from both mice and humans. We found that the NF-κB pathway was regulated by miR-21, and that A20 was a direct target of miR-21. Furthermore, miR-21 deficiency inhibited the ASC pyroptosome, which restrained caspase-1 activation and GSDMD cleavage, thereby preventing LPS-induced pyroptosis and septic shock. miR-21 deficiency resulted in an increase in A20, which led to decreased IL-1β production and caspase-1 activation. Caspase-1-mediated GSDMD cleavage was consequently decreased, which prevented pyroptosis in LPS-induced sepsis in mice. Our results demonstrate that miR-21 is a critical positive regulator of the NF-κB pathway and NLRP3 inflammasomes in pyroptosis and septic shock via A20. In addition, by analyzing published miRNA expression profiles in the Gene Expression Omnibus database, we found that the miR-21 levels in peripheral blood from patients with septic shock were elevated. Thus, miR-21 may serve as a potential treatment target in patients with septic shock.
Dear Editor, Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) are three major types of skin cancer. Among them, melanoma is the most severe form and accounts for~4% of all newly diagnosed cancers annually in the United States. It is estimated that approximately 9500 people are diagnosed with skin cancer every day, and more than 1 million Americans are living with melanoma. Melanoma treatment is still a major challenge in the clinic. Photodynamic therapy (PDT) is composed of targeted ablation and immune activation, is less invasive than other therapies and has been widely used in the treatment of various cancers. However, the limitation of light penetration is an issue in PDT for deep cancer treatment. 1 To overcome this limitation and enable PDT for deep cancer treatment, researchers have proposed X-ray-induced PDT 1 and nanoparticle self-lighting PDT, 2 and these techniques have become intensively studied topics. Recently, Chen et al. 3 invented a new sensitizer called copper-cysteamine (Cu-Cy) that can be activated by UV, 4 X-rays, 5 microwave, 6 and ultrasound 7 to generate reactive oxygen species (ROS) to destroy cancer cells as well as bacteria. 8 As ROS generation by Cu-Cy nanoparticles (NPs) is not solely activated by regular light, it is more appropriate to call it oxidative therapy (OT) rather than PDT. Cu-Cy NPs of an average size of 96 nm have been tested for skin cancer treatment. 9 It was found that these Cu-Cy NP-based X-PDT exhibited a strong antitumor effect towards SCC. However, B16F10 melanoma was resistant to these Cu-Cy NP-based X-PDT, both in vitro and in vivo. 9 Size is known to be a sensitive factor influencing nanomaterial properties and performance. To further evaluate the effect of Cu-Cy NP-based X-PDT on melanoma, we applied particles with an average size of~40 nm for the treatment of melanoma, as the 40 nm Cu-Cy NPs have a larger surface area than other NPs, thereby producing more ROS. 10 In addition, the cell uptake is higher for the 40 nm NPs. As expected, the 40 nm Cu-Cy NPs were very effective in inhibiting melanoma under X-ray stimulation. These observations confirmed that the combination of Cu-Cy and X-rays facilitated cell apoptosis and/or necrosis of B16 cells. More interestingly, this combination promoted the formation of the antitumor immune response. These results suggest that Cu-Cy NPs can simultaneously facilitate radiotherapy, oxidative therapy, and immunotherapy for melanoma treatment, as illustrated in Fig. 1a. The distribution of Cu-Cy was assessed by confocal fluorescence microscopy. As shown in Supplementary Fig. S1, the uptake of Cu-Cy NPs in the nucleus after 6 h was substantially increased compared to that after 2 and 4 h of incubation. Next, the cytotoxicity was measured to assess the efficacy of Cu-Cy on B16 cells by the CCK8 viability assay. After incubation with various amounts of Cu-Cy for 24 h, the cells were irradiated with X-rays at
Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.
BackgroundImmune checkpoint blockade has emerged as a potential cancer immunotherapy. The “don’t eat me” signalCD47in cancer cells binds signal regulatory protein-α on macrophages and prevents their phagocytosis. The role of miR-340 in pancreatic ductal adenocarcinoma (PDAC), especially in tumor immunity, has not been explored. Here, we examined the clinical and biological relevance of miR-340 and the molecular pathways regulated by miR-340 in PDAC.MethodsCD47and miR-340 expression and the relationship with cancer patient survival were analyzed by bioinformatics. The mechanism of miR-340 action was explored through bioinformatics, luciferase reporter, qRT-PCR and western blot analyses. The effects of miR-340 on cancer cells were analyzed in terms of apoptosis, proliferation, migration and phagocytosis by macrophages.In vivotumorigenesis was studied in orthotopic and subcutaneous models, and immune cells from the peripheral and tumor immune microenvironments were analyzed by flow cytometry. Depletion of macrophages was used to verify the role of macrophages in impacting the function of miR-340 in tumor progression.ResultsmiR-340 directly regulates and inversely correlates withCD47,and it predicts patient survival in PDAC. The restoration of miR-340 expression in pancreatic cancer cells was sufficient to downregulateCD47and promote phagocytosis of macrophages, further inhibiting tumor growth. The overexpression of miR-340 promoted macrophages to become M1-like phenotype polarized in peripheral and tumor immune microenvironments and increased T cells, especially CD8+T cells, contributing to the antitumor effect of miR-340.ConclusionsmiR-340 is a key regulator of phagocytosis and antitumor immunity, and it could offer a new opportunity for immunotherapy for PDAC.
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