Checkpoint blockade immunotherapy has demonstrated significant clinical success in various malignant tumors. However, the therapeutic response is limited due to the immunosuppressive tumor microenvironment (ITM). In this study, a functional nanomaterial, layered double hydroxides (LDHs), carrying specific functional miR155 is developed to modulate ITM by synergistically repolarizing tumor associated macrophages (TAMs) to M1 subtype. LDH nanoparticles loaded with miR155 (LDH@155) exhibit superior ability in cellular uptake by murine macrophages, miR escape into the cytoplasm and TAMs specific delivery when introtumoral administration. Meanwhile, upon exposure to LDH@155, TAMs are significantly skewed to M1 subtype, which markedly inhibits myeloid-derived suppressor cells (MDSCs) formation and stimulates T-lymphocytes to secrete more interferon-γ (IFN-γ) cytokines in vitro. Introtumoral administration of LDH@155 reduces the percentage of TAMs and MDSCs in the tumor and elevates CD4
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.
Macrophage-mediated inflammation has a significant bursting period and restoring period, which suggests the presence of intrinsic anti-inflammatory mechanisms. Here, we reported a dynamic regulator, cytoplasmic deoxyguanosine kinase (dGK), in the process of macrophage polarization and homeostasis. Firstly, we confirmed a positive correlation between dGK and the procedure of classically activated macrophages polarization. Moreover, dGK was proved to maintain STAT1 phosphorylation via binding the C-terminal domain of STAT1, which facilitated STAT1-Jak2 interaction and simultaneously blocked interaction with the phosphatase, TC45, during initial phase of proinflammatory macrophage polarization. However, in the inflammation resolution phase, macrophage suffered from increased autophagy which consequently restrained proinflammatory phenotype by inducing the degradation of dGK. Further we screened a variety of small molecules and found that PMFA ameliorated inflammation depending on autophagy-mediated dGK degradation. These findings revealed the dynamic regulation mode of dGK during classically activated macrophage polarization and the maintained immune homeostasis.
CpG ODN acts as a 'pathogen-associated' molecular pattern that is recognized by intracellular Toll-like receptor 9 and can induce a robust dendritic cells (DCs) activation to against various diseases. However, the CpG ODN is restricted with critical defects of easily enzymolysis and negligible phagocytosis. To overcome these issues, a simpler and competent nanocarrier of mannose modified PEGylated branched PEI25k (PEI-PEG-Man) was designed to achieve excellent DCsspecific delivery of CpG. Nanoparticles of PEI-PEG-Man encapsulating CpG (PEI-PEG-Man@CpG) possessed elevated gene loading capacity, biological stability and admirable anti-enzymolysis ability. PEI-PEG-Man@CpG could be selectively uptake by DCs through a receptor-mediated endocytosis, which generates a potent immunostimulatory activity on bone marrow derived dendritic cells (BMDCs) evidenced by significantly upregulation of the pro and anti-inflammatory cytokines (TNF-α, IL-6) and the co-stimulatory molecules (CD40, CD80, CD86, and MHC class II) on BMDCs in vitro. More importantly, the results of in vivo targeting assay showed that PEI-PEG-Man@CpG nanoparticles could remarkably boost CpG accumulation in lymph lodes upon subcutaneous administration in C57BL/6 mice, which facilitated maturation of DCs and productions of anti-inflammatory cytokines. Our results suggested that PEI-PEG-Man@CpG nanoparticles, in the future, might function as a powerful vector for ex vivo engineering to promote DC targeting and maturation, which enhance vaccine efficiency against cancer or infectious disease.
Recent studies suggest that change of macrophage phenotype (M1/M2) is associated with autoimmune diseases. Sodium valproate (VPA) is a class I histone deacetylase (HDAC) inhibitor, which has immunomodulatory function in graft-versus-host disease. However, its impact on macrophage polarization has not been defined. We evaluated the effects of VPA on both mouse macrophage cell line RAW264.7 and primary mouse bone marrow macrophages (BMMs). Exposure to VPA significantly repressed the production of interleukin 12 (IL-12), and tumor necrosis factor α by lipopolysaccharide (LPS)-induced macrophage activation, in contrast, promoted IL-10 expression. VPA also affected the costimulatory molecule expression on LPS-stimulated RAW264.7 and BMMs (downregulation of CD40 and CD80, and upregulation of CD86). Specifically, VPA inhibited macrophage-mediated T helper 1 (Th1) effector but enhanced Th2 effector cell activation. Together, our preclinical study demonstrates that VPA significantly affects the phenotype and function of macrophage, indicating an important role of HDAC activity in immune regulation and inflammation. It also provides a rationale to evaluate VPA activity for the treatment of macrophage dysfunction-associated diseases.
Abstract The role of specific histone deacetylase ( HDAC ) proteins in regulating the lipopolysaccharide ( LPS )‐induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC 2, a class I HDAC family protein, is essential for the LPS ‐triggered inflammatory response in macrophages. LPS stimulation increases HDAC 2 expression in macrophages. Knockdown of HDAC 2 decreases the expression of proinflammatory genes, such as IL ‐12, TNF ‐α and iNOS following stimulation with LPS . The adoptive transfer of HDAC 2 knockdown macrophages attenuates the LPS ‐triggered innate inflammatory response in vivo , and these mice are less sensitive to endotoxin shock and Escherichia coli ‐induced sepsis. Mechanistically, the c‐Jun protein is the main target of HDAC 2‐mediated LPS ‐induced production of proinflammatory cytokines. Moreover, HDAC 2 knockdown increases the expression of c‐Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c‐Jun expression. According to the chromatin immunoprecipitation analysis, HDAC 2 also selectively suppresses c‐Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC 2/c‐Jun signaling network that regulates the LPS ‐induced immune response in macrophages.
Background: Obesity is defined as a chronic, low-grade inflammatory disease that can cause obesity-associated disorders, such as cancer. Obesity has traditionally been thought to be a risk factor for ovarian cancer. Few reports have focused on the specific pathogenesis of obesity-related ovarian cancer. When considering the correlation between obesity and the relative risk of death from ovarian cancer, we investigated whether obesity promotes tumor immune escape in ovarian cancer. Results: In the present study, obese mice were found to have higher rates of tumor growth and tumor infiltration than mice of normal weight. Obesity increased the proportion of myeloid-derived suppressor cells (MDSCs) in peripheral blood compared with mice of normal weight. In addition, the levels of CCL25, CD40L, GM-CSF, IL-5, IGFBP2, IL-6, MMP3, and MMP9 in the peripheral blood, bone marrow, and ovarian tissue of obese mice were higher than in mice of normal weight. Moreover, IL-5 and IL-6 significantly enhanced the expression levels of S100A8 and S100A9 in MDSCs. When compared with the levels in mice of normal weight, the expression levels of S100A8 and S100A9 in the MDSCs of OB/OB mice were also higher within the tumor microenvironment. The infiltration of MDSCs in ovarian cancer was found to be positively correlated with the expression levels of IL-6. The IL-6 expression levels in ovarian cancer tissue are positively correlated with the expression levels of S100A8 and S100A9, which is consistent with the results of previous animal experiments. Finally, we found that LMT28 can suppress the tumor growth by inhibiting IL-6. Conclusion: Obesity promotes the expression of the MDSC-related immunosuppressive genes S100A8 and S100A9 by upregulating IL-6, thus promoting tumor immune evasion and metastasis in ovarian cancer. Keywords: ovarian cancer, obesity, MDSCs, IL-6
The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages.
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