Catalpol Inhibits Macrophage Polarization and Prevents Postmenopausal Atherosclerosis Through Regulating Estrogen Receptor Alpha

Lacking estrogen increases the risk of atherosclerosis (AS) in postmenopausal women. Inflammation plays a vital role in the pathological process of AS, and macrophages are closely related to inflammation. Catalpol is an iridoid glucoside extracted from the fresh roots of the traditional Chinese herb Rehmanniae radix preparata. In this study, we aimed to evaluate the effects of catalpol on macrophage polarization and postmenopausal AS. In addition, we investigated whether the mechanism of catalpol was dependent on regulating the expression of estrogen receptors (ERs). In vitro, lipopolysaccharides (LPS) and interferon-γ (IFN-γ) were applied to induce M1 macrophage polarization. In vivo, the ApoE−/− mice were fed with a high-fat diet to induce AS, and ovariectomy was operated to mimic the estrogen cessation. We demonstrated catalpol inhibited M1 macrophage polarization induced by LPS and INF-γ, and eliminated lipid accumulation in postmenopausal AS mice. Catalpol not only suppressed the inflammatory response but also reduced the level of oxidative stress. Then, ERs (ERα and ERβ) inhibitors and ERα siRNA were also applied in confirming that the protective effect of catalpol was mediated by ERα, rather than ERβ. In conclusion, catalpol significantly inhibited macrophage polarization and prevented postmenopausal AS by increasing ERα expression.

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Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma

Genome Biology ◽

10.1186/s13059-021-02308-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jie Yu ◽

Peiwei Chai ◽

Minyue Xie ◽

Shengfang Ge ◽

Jing Ruan ◽

...

Keyword(s):

Macrophage Polarization ◽

Regulation Of Gene Expression ◽

Metabolic Stress ◽

Ocular Melanoma ◽

Rna Modifications ◽

M1 Macrophage ◽

Melanoma Therapy

Abstract Background Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Results Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. Conclusion We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

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In vivo and In vitro PPAR-y Activation Decreases M1-Macrophage Polarization and Improves Liver Ischemia Reperfusion Injury

Transplantation Journal ◽

10.1097/01.tp.0000543674.85457.9b ◽

2018 ◽

Vol 102 ◽

pp. S708

Author(s):

Ivan Linares ◽

Agata Bartczak ◽

Kaveh Farrokhi ◽

Dagmar Kollmann ◽

Moritz Kaths ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Macrophage Polarization ◽

Liver Ischemia ◽

M1 Macrophage

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Kaempferol Alleviates Corneal Transplantation Rejection by Inhibiting NLRP3 Inflammasome Activation and Macrophage M1 Polarization via Promoting Autophagy

10.21203/rs.3.rs-368448/v1 ◽

2021 ◽

Author(s):

Huiwen Tian ◽

Shumei Lin ◽

Jing Wu ◽

Ming Ma ◽

Jian Yu ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Macrophage Polarization ◽

Corneal Transplantation ◽

Inflammasome Activation ◽

M1 Polarization ◽

Nlrp3 Inflammasome Activation ◽

M1 Macrophage ◽

Transplantation Rejection

Abstract Corneal transplantation rejection remains a major threat to the success rate in high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the relationship between kaempferol and corneal transplantation remains largely unexplored. To address this, both in vivo and in vitro, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model in THP-1 derived human macrophages. In the transplantation experiments, we observed an enhancement in the NLRP3 / IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol can reduce the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed the effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of the NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol could be used as a potential therapeutic agent in the treatment of allograft rejection.

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The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice

Blood ◽

10.1182/blood.2019003990 ◽

2020 ◽

Vol 136 (4) ◽

pp. 501-515 ◽

Cited By ~ 8

Author(s):

Kunpeng Wu ◽

Yan Yuan ◽

Huihui Yu ◽

Xin Dai ◽

Shu Wang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Macrophage Polarization ◽

Short Chain Fatty Acids ◽

Inflammasome Activation ◽

Microbial Metabolites ◽

M1 Macrophage ◽

The Impact

Abstract The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow–derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage’s response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

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The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012495 ◽

2020 ◽

Vol 295 (20) ◽

pp. 7018-7032 ◽

Cited By ~ 2

Author(s):

Guibin Fang ◽

Yuan Fu ◽

Shixun Li ◽

Junxiong Qiu ◽

Manyuan Kuang ◽

...

Keyword(s):

Macrophage Polarization ◽

Wear Particle ◽

Wear Particles ◽

Titanium Particle ◽

Pathway Activation ◽

M1 Macrophage ◽

Phosphoinositide 3 Kinase ◽

Factor Α

Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

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Anti-Inflammatory Effect of Curcumin on the Mouse Model of Myocardial Infarction through Regulating Macrophage Polarization

Mediators of Inflammation ◽

10.1155/2021/9976912 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Shaoxi Yan ◽

Mo Zhou ◽

Xiaoyun Zheng ◽

Yuanyuan Xing ◽

Juan Dong ◽

...

Keyword(s):

Myocardial Infarction ◽

Ventricular Remodeling ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M1 Macrophages ◽

Macrophage Marker ◽

M1 Macrophage ◽

Anti Inflammatory

Inflammation causes tissue damage and promotes ventricular remodeling after myocardial infarction (MI), and the infiltration and polarization of macrophages play an important role in regulating inflammation post-MI. Here, we investigated the anti-inflammatory function of curcumin after MI and studied its relationship with macrophage polarization. In vivo, curcumin not only attenuated ventricular remodeling 3 months after MI but also suppressed inflammation during the first 7 days post-MI. Importantly, the results of qPCR and immunochemistry showed that curcumin decreased M1 (iNOS, CCL2, and CD86) but increased M2 macrophage (Arg1, CD163, and CD206) marker expression in the myocardium of MI mice during the first 7 days post-MI. And flow cytometry analysis indicated that curcumin suppressed M1 (CD45+Gr-1-CD11b+iNOS+ cells) but enhanced M2 macrophage (CD45+Gr-1-CD11b+Arg+ cells) expansion in the myocardium of MI mice during the first 7 days post-MI. In vitro, curcumin decreased LPS/IFNγ-elevated M1 macrophage marker (iNOS and CD86) expression and the proportion of M1 macrophages (iNOS+F4/80+ cells) but increased LPS/IFNγ-suppressed M2 macrophage marker (Arg1 and CD206) expression and the proportion of M2 macrophages (Arg1+F4/80+ cells). In addition, curcumin modulates M1/M2 macrophage polarization partly via AMPK. In conclusion, curcumin suppressed the MI-induced inflammation by modulating macrophage polarization partly via the AMPK pathway.

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Neutrophil-Derived Exosomes Induce M1 Macrophage Polarization and Prime Macrophage Pyroptosis via miR-30d-5p in Sepsis

10.21203/rs.3.rs-665364/v1 ◽

2021 ◽

Author(s):

Yang Jiao ◽

Ti Zhang ◽

Chengmi Zhang ◽

Haiying Ji ◽

Xingyu Tong ◽

...

Keyword(s):

Macrophage Activation ◽

Macrophage Polarization ◽

Cecal Ligation ◽

Polymorphonuclear Neutrophils ◽

Raw264.7 Macrophages ◽

M1 Macrophage ◽

Tnf Α

Abstract Background: Polymorphonuclear neutrophils (PMNs) have been demonstrated to play a role in proinflammatory M1 activation and macrophage (Mϕ) pyroptosis in sepsis. Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis remains unclear. This study aimed to determine whether PMN-derived exosomes play a role in proinflammatory M1 activation and Mϕ pyroptosis in sepsis and explore the potential mechanisms involved. Methods: Exosomes were isolated from the supernatant of PMNs activated with phosphate buffered saline (PBS) or tumor necrosis factor (TNF)-α, cocultured with Raw264.7 macrophages or BMDMs, and then assayed for macrophage polarization and pyroptosis. To examine the role of exosomes in vivo, PMN-derived exosomes were administered to mice, and then examined for lung inflammation. Results: After activated by TNF-α, PMNs released exosomes (TNF-Exo) to promote M1 macrophage activation both in vivo and in vitro. In addition, TNF-Exo primed macrophages for pyroptosis by upregulating NLRP3 inflammasome expression through NF-κB signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting SOCS-1 and SIRT1 in macrophages. Furthermore, treatment of miR-30d-5p inhibitors in vivo significantly decreased cecal ligation and puncture (CLP) or TNF-Exo-induced M1 macrophage activation and macrophage death in the lung. Lung injury was also alleviated by miR-30d-5p inhibitors.Conclusions: In this study, we identified a novel mechanism of PMN-Mϕ interaction in sepsis, demonstrating that exosomal miR-30d-5p from PMNs induced M1 macrophage polarization and primed Mϕ for pyroptosis by activating NF-κB signaling. These findings suggest a previously unidentified role of neutrophil-derived exosomes in sepsis and may lead to new therapeutic approaches.

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Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001657 ◽

2021 ◽

Vol 9 (3) ◽

pp. e001657

Author(s):

Da-Liang Ou ◽

Chia-Wei Chen ◽

Chia-Lang Hsu ◽

Chih-Hung Chung ◽

Zi-Rui Feng ◽

...

Keyword(s):

T Cells ◽

Antitumor Immunity ◽

Macrophage Polarization ◽

Antitumor Efficacy ◽

Immunomodulatory Effects ◽

P38 Kinase ◽

M2 Polarization ◽

M1 Macrophage

BackgroundRegorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined.MethodsIn vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow–derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation.ResultsRegorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.ConclusionRegorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic.

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Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Cell Death and Disease ◽

10.1038/s41419-020-03385-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ying Zhang ◽

Conghui Zhang ◽

Lixi Li ◽

Xinjun Liang ◽

Peng Cheng ◽

...

Keyword(s):

Renal Fibrosis ◽

Macrophage Polarization ◽

Lymphatic Vessels ◽

Macrophage Phenotype ◽

M1 Macrophages ◽

M1 Macrophage ◽

Close Relationship ◽

Stage Renal Disease

AbstractInflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

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Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

Cell Death and Disease ◽

10.1038/cddis.2017.102 ◽

2017 ◽

Vol 8 (5) ◽

pp. e2763-e2763 ◽

Cited By ~ 16

Author(s):

Jing Zhong ◽

Huihui Wang ◽

Wankun Chen ◽

Zhirong Sun ◽

Jiawei Chen ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Toll Like Receptor ◽

M1 Macrophage ◽

M2 Macrophage Polarization ◽

P38 Pathway

Abstract Sepsis is a systemic inflammation caused by infection. The balance between M1–M2 macrophage polarization has an essential role in the pathogenesis of sepsis. However, the exact mechanism underlying macrophage polarization is unclear. We previously showed that levels of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) were significantly elevated in septic patients compared with those in nonseptic patients, and involved in the activation of Toll-like receptor (TLR) 2/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB pathway. In the present study, we explored whether MFHAS1 was involved in macrophage polarization and determined the effect of MFHAS1 on inflammation. We performed in vitro pulldown assays and in vivo co-immunoprecipitation assays and found that E3 ubiquitin ligase praja2 could directly bind to MFHAS1. In situ immunostaining analysis confirmed the colocalization of endogenous praja2 with MFHAS1. We first reported that praja2 promotes the accumulation of ubiquitylated MFHAS1 but does not degrade it. Moreover, our results indicate that MFHAS1 ubiquitylation by praja2 positively regulates TLR2-mediated JNK/p38 pathway and promotes M1 macrophage polarization, M2 to M1 macrophage transformation and inflammation.

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