Autophagy deficiency promotes M1 macrophage polarization to exacerbate acute liver injury via ATG5 repression during aging

AbstractAging disrupts the maintenance of liver homeostasis, which impairs hepatocyte regeneration and aggravates acute liver injury (ALI), ultimately leading to the development of acute liver failure (ALF), a systemic inflammatory response, and even death. Macrophages influence the progression and outcome of ALI through the innate immune system. However, it is still unclear how macrophages regulate ALI during aging. The variation in macrophage autophagy with aging and the influence on macrophage polarization and cytokine release were assessed in BMDMs in vitro. Then, after BMDMs subjected to several treatments were intravenously or intraperitoneally injected into mice, thioacetamide (TAA)-induced ALI (TAA-ALI) was established, and its effects on inflammation, injury, and mortality were assessed. We found that aging aggravated the liver injury, along with increases in the levels of proinflammatory mediators, presenting a senescence-associated secretory phenotype (SASP), which promoted macrophage polarization to the M1 phenotype. In addition, autophagy levels decreased significantly in aged mice, which was ascribed to ATG5 repression during aging. Notably, enhancing autophagy levels in aged BMDMs restored macrophage polarization to that observed under young conditions. Finally, autophagy restoration in aged BMDMs enhanced the protective effect against TAA-ALI, similar to M2 macrophages induced by IL-4. Overall, we demonstrated that the influence of aging on macrophage polarization is an important aggravating factor in TAA-ALI, and the autophagy in macrophages is associated with the aging phenotype.

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PICK1 confers anti-inflammatory effects in acute liver injury via suppressing M1 macrophage polarization

Biochimie ◽

10.1016/j.biochi.2016.05.002 ◽

2016 ◽

Vol 127 ◽

pp. 121-132 ◽

Cited By ~ 7

Author(s):

Juan Xie ◽

Xiaoqin Wu ◽

Qun Zhou ◽

Yang Yang ◽

Yuanyao Tian ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Macrophage Polarization ◽

M1 Macrophage ◽

Anti Inflammatory

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A Benzenediamine Analog FC-99 Drives M2 Macrophage Polarization and Alleviates Lipopolysaccharide- (LPS-) Induced Liver Injury

Mediators of Inflammation ◽

10.1155/2019/7823069 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Wei Gong ◽

Haiyan Zhu ◽

Li Lu ◽

Yayi Hou ◽

Huan Dou

Keyword(s):

Liver Injury ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M1 Macrophage ◽

M2 Macrophage Polarization ◽

Underlying Mechanisms ◽

Sirna Knockdown ◽

Lower Expression ◽

Alternatively Activated

Macrophages have variable functional phenotypes, high diversity, and plasticity and are involved in the pathogenesis of sepsis-induced liver injury. Alteration of macrophage polarization through activated (M1) macrophage to alternatively activated (M2) macrophage has emerged as a potential therapeutic strategy. This study was designed to explore the effect of a benzenediamine analog FC-99 on macrophage polarization in vitro and lipopolysaccharide- (LPS-) induced liver injury followed by the underlying mechanisms. For in vitro experiments, FC-99 inhibited M1-related macrophage factors and promoted M2-related markers induced by IL-4 in the mouse macrophage cell line RAW264.7. Moreover, FC-99-induced macrophages polarized to M2 phenotype which could be repressed by a PPAR-γ inhibitor but not STAT6 siRNA knockdown, indicating FC-99-induced M2 macrophage polarization through PPAR-γ rather than STAT6 signal. In LPS-induced septic mice, FC-99 pretreated mice displayed lower expression of M1 markers together with the increased M2 marker CD206 and improvement of liver injury. These findings illustrated that FC-99 could promote M2 macrophage polarization via PPAR-γ signaling and seemed to be a potential therapeutic candidate for inflammatory liver injury.

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MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

Frontiers in Medicine ◽

10.3389/fmed.2021.752223 ◽

2021 ◽

Vol 8 ◽

Author(s):

Wei Yan ◽

Yingchun Shen ◽

Jinny Huang ◽

Ling Lu ◽

Qian Zhang

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Acute Liver Injury ◽

Macrophage Polarization ◽

Suppressor Cells ◽

Suppressor Cell ◽

Pathological Process ◽

M2 Macrophage ◽

Pyrin Domain ◽

M1 Macrophage

Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

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Effect of Cocoa Polyphenolic Extract on Macrophage Polarization from Proinflammatory M1 to Anti-Inflammatory M2 State

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/6293740 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Laura Dugo ◽

Maria Giovanna Belluomo ◽

Chiara Fanali ◽

Marina Russo ◽

Francesco Cacciola ◽

...

Keyword(s):

Macrophage Polarization ◽

Total Phenolic ◽

Macrophage Response ◽

Beneficial Effects ◽

Polyphenolic Extract ◽

M1 Macrophage ◽

Inflammatory State ◽

M1 Phenotype ◽

Anti Inflammatory

Polyphenols-rich cocoa has many beneficial effects on human health, such as anti-inflammatory effects. Macrophages function as control switches of the immune system, maintaining the balance between pro- and anti-inflammatory activities. We investigated the hypothesis that cocoa polyphenol extract may affect macrophage proinflammatory phenotype M1 by favoring an alternative M2 anti-inflammatory state on macrophages deriving from THP-1 cells. Chemical composition, total phenolic content, and antioxidant capacity of cocoa polyphenols extracted from roasted cocoa beans were determined. THP-1 cells were activated with both lipopolysaccharides and interferon-γfor M1 or with IL-4 for M2 switch, and specific cytokines were quantified. Cellular metabolism, through mitochondrial oxygen consumption, and ATP levels were evaluated. Here, we will show that cocoa polyphenolic extract attenuated in vitro inflammation decreasing M1 macrophage response as demonstrated by a significantly lowered secretion of proinflammatory cytokines. Moreover, treatment of M1 macrophages with cocoa polyphenols influences macrophage metabolism by promoting oxidative pathways, thus leading to a significant increase in O2consumption by mitochondrial complexes as well as a higher production of ATP through oxidative phosphorylation. In conclusion, cocoa polyphenolic extract suppresses inflammation mediated by M1 phenotype and influences macrophage metabolism by promoting oxidative pathways and M2 polarization of active macrophages.

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5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction

International Journal of Molecular Sciences ◽

10.3390/ijms22031083 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1083

Author(s):

Sukkum Ngullie Chang ◽

Se Ho Kim ◽

Debasish Kumar Dey ◽

Seon Min Park ◽

Omaima Nasif ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Elevated Serum ◽

In Vitro Study ◽

Biological Properties ◽

Autophagic Flux ◽

Serum Aminotransferase ◽

Ccl4 Treatment

Polymethoxyflavanoids (PMFs) have exhibited a vast array of therapeutic biological properties. 5-O-Demethylnobiletin (5-DN) is one such PMF having anti-inflammatory activity, yet its role in hepatoprotection has not been studied before. Results from in vitro study revealed that 5-DN did not exert a high level of cytotoxicity on HepG2 cells at 40 μM, and it was able to rescue HepG2 cell death induced by carbon tetrachloride (CCl4). Subsequently, we investigated acute liver injury on BALB/c mice induced by CCl4 through the intraperitoneal injection of 1 mL/kg CCl4 and co-administration of 5-DN at (1 and 2 mg/kg) by oral gavage for 15 days. The results illustrated that treatment with 5-DN attenuated CCl4-induced elevated serum aminotransferase (AST)/alanine aminotransferase (ALT) ratio and significantly ameliorated severe hepatic damage such as inflammation and fibrosis evidenced through lesser aberrations in the liver histology of 5-DN dose groups. Additionally, 5-DN efficiently counteracted and equilibrated the production of ROS accelerated by CCl4 and dramatically downregulated the expression of CYP2E1 vitally involved in converting CCl4 to toxic free radicals and also enhanced the antioxidant enzymes. 5-DN treatment also inhibited cell proliferation and inflammatory pathway abnormally regulated by CCl4 treatment. Furthermore, the apoptotic response induced by CCl4 treatment was remarkably reduced by enhanced Bcl-2 expression and noticeable reduction in Bax, Bid, cleaved caspase 3, caspase 9, and apaf-1 expression. 5-DN treatment also induced the conversion of LC3 and promoted the autophagic flux. Conclusively, 5-DN exhibited hepatoprotective effects in vitro and in vivo and prevented liver fibrosis induced by CCl4.

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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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847 Inflammasome activation in M2 macrophage restrain the immune suppressive function

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0847 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A900-A900

Author(s):

Ronghua Zhang ◽

Tienan Wang ◽

Qing Lin

Keyword(s):

T Cell ◽

T Cell Activation ◽

Culture System ◽

Cell Activation ◽

Macrophage Polarization ◽

Inflammasome Activation ◽

M2 Macrophage ◽

M1 Macrophage ◽

Suppressive Phenotype

BackgroundMacrophage is an important component in tumor microenvironment (TME) and plays multiple roles in tumor initiation, progression and metastases. In response to various stimuli within TME, macrophage exhibits high level of functional heterogeneity. There are two distinct groups of macrophages: M1 macrophage exhibits pro-inflammatory phenotype with high levels of TNF-a, IL-6, and IL-1ß, while M2 macrophage displays immune suppressive phenotype with high levels of anti-inflammatory cytokines such as IL-10 and TGF-ß. In response to the M2 cytokines, myeloid cells within the TME further acquire higher expression of PD-L1 and thus inactivate T cells. M2 cytokines can also directly inhibit T cell activation. As a result, re-polarizing M2 macrophages becomes a key concept for cancer immunotherapy. The NLRP3 inflammasome is acquired by macrophages to fight against endogenous danger signals. Macrophage NLRP3 activation has been observed in several tumor models, but the function of NLRP3 on macrophage polarity remains controversial. Inflammasome activation with IL-1ß/IL-18 secretion was reported to promote M1 polarization. However, NLRP3 activation was also reported to promote M2 polarity through up-regulation of IL4 in asthma modelMethodsHere, we have established an in vitro human macrophage NLRP3 activation system (figure 1), coupled with M2 macrophage polarization assay, to dissect the role of NLRP3 in macrophage phenotype.ResultsOur results indicate that NLRP3 activation restrained M2 phenotype and further enhanced T cell activation in an M2/T cell co-culture system (figure 2).Abstract 847 Figure 1Inflammasome activation polarize M2 macrophage intUse LPS/ATP to stimulate NLRP3 in M2 macrophage and demonstrate NLRP3 activation could reduce CD163 and increase CD86Abstract 847 Figure 2Inflammasome in M2 rescue T cell activationestablish M2/T co-culture system in vitro to demonstrate M2 could suppress T activation while Inflammatory M2 could partial rescue the suppressive phenotypeConclusionsInflammasome could be the potential target for cancer by modulating T cell activation through macrophage polarization regulation

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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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Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways

10.21203/rs.3.rs-60253/v1 ◽

2020 ◽

Author(s):

Jiansen Lu ◽

Hongbo Zhang ◽

Jianying Pan ◽

Zhiqiang Hu ◽

Liangliang Liu ◽

...

Keyword(s):

Macrophage Polarization ◽

In Vitro Study ◽

Cartilage Degeneration ◽

Research Society ◽

Preventive Strategy ◽

Protective Effects ◽

Erk Mapk ◽

M1 Macrophage ◽

Main Components

Abstract Synovial macrophage polarization and interactions between chondrocytes and macrophages are essential for osteoarthritis (OA) development. The present study determined the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium. 10-week-old male C57BL/6 mice were randomly assigned to sham-operated, collagenase-induced OA (CIOA)-operated, or CIOA-operated with intraarticular fargesin treatment groups. Fargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by down-regulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Although conditioned medium (CM) from the M1 macrophage treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, and type X collagen X in OA cartilage, it had no direct effect on chondrocyte metabolism in an in vitro study. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling. This study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by down-regulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.

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