A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo

Jiménez-García, Lidia; Higueras, María Ángeles; Herránz, Sandra; Hernández-López, Marta; Luque, Alfonso; Herrero, Beatriz de las Heras; Hortelano, Sonsoles

doi:10.1016/j.bcp.2018.06.002

Cited by 33 publications

(20 citation statements)

References 38 publications

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“…Repolarization of TAMs from anti- to pro-inflammatory phenotype is associates with increased TNF-α, but attenuated TGF-β 23. JAK/STAT signaling pathway is also closely associated with macrophage polarization 54, 55. IL-6 secreted by TAMs is highly correlated with the occurrence and development of hepatic carcinoma via activating STAT3 pathway 56.…”

Section: Discussionmentioning

confidence: 99%

Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells

Miao

Zhao

et al. 2020

Theranostics

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Rationale:STING is a critical player in the innate and adaptive immune system, sensing cytosolic DNA to activate the expression of interferon genes and regulate T lymphocytes, which drives immunogenic responses to cancer cells. Tumor-associated macrophages (TAMs), abundantly present in the tumor microenvironment, play a key role in cancer development. Gastric cancer is one of the most common and leading causes in cancer-related death worldwide. However, studies on the function and regulation of STING in TAMs and their roles in gastric cancer progression are still limited.Methods: We analyzed STING and CD68 expression of 200 pairs of gastric cancer and adjacent normal tissues by immunohistochemistry to identify the prognostic values of STING, as well as the correlations between STING and CD68 in gastric cancer. The characteristics of STING-altered macrophages, as well as their effects on cancer cell apoptosis and T cell differentiation were examined by flow cytometry. Cytokines secreted by STING-altered macrophages were identified by the Human Inflammation Array3 kit. Concentrations of soluble IL24 and IFN-β were measured by ELISA. In vivo models, including spontaneous gastric cancer in p53+/- mice and cell line-based xenografts, were established, and clinical benefits of STING-altered macrophages were examined.Results: Our study identifies STING as a prognostic factor for gastric cancer, and for the first time demonstrated that knocking-down STING and STING activation by 2'3'-c-GAMP both promote TAMs polarizing into pro-inflammatory subtype and induce apoptosis of gastric cancer cells, mechanistically through IL6R-JAK-IL24 pathway.Conclusions: This study evaluated effects of targeting STING in TAMs in anti-gastric-cancer therapies. Moreover, we unveil a novel function of STING to activate the IL6R-JAK-IL24 pathway in macrophages.

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Section: Discussionmentioning

confidence: 99%

Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells

Miao

Zhao

et al. 2020

Theranostics

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“…Gene ablation experiments showed that Akt1 and 2 interact to regulate M1 and M2 macrophage polarization 44 . JAK/STAT pathways are also involved in macrophage polarization 45 . It has also been found that metformin can promote M1 macrophages and inhibit M2 macrophages through the Notch signaling pathway, finally inhibiting the growth of liver cancer cells 46 .…”

Section: Discussionmentioning

confidence: 99%

Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Zhang

et al. 2021

Nat Commun

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Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats−/− mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats−/− mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats−/− macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.

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“…A DAB Peroxidase Substrate Kit (Vector Labs) was used to visualize peroxidase reaction. The number of CD163 + , CD80 + and F4/80 + macrophages was quantified microscopically for each slide from 5-10 randomly chosen fields of five independent mice, as previously described [84]. All images were captured with a microscope (BX51, OLYMPUS, JAPAN) and analyzed by a blinded observer with ImageJ.…”

Section: Immunohistochemical (Ihc) Analysismentioning

confidence: 99%

Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice

Frazier

Spahiu

et al. 2020

Aging

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Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knockout mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.

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A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo

Cited by 33 publications

References 38 publications

Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells

Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells

Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice

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