Toll-like receptor 4 plays a key role in advanced glycation end products-induced M1 macrophage polarization

Liu, Zhongwei; Ma, Yanpeng; Cui, Qianwei; Xu, Jing; Tang, Zhiguo; Wang, Yuan; He, Chunhui; Wang, Xi

doi:10.1016/j.bbrc.2020.08.014

Cited by 34 publications

(30 citation statements)

References 23 publications

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“…The inflammatory cascade, as a primary immune response, is a function carried out mainly by macrophages in synergy with the toll-like receptor family, especially toll-like receptor 4 (TLR4), which binds the ligand lipopolysaccharide (LPS), initiating the signaling pathway [10]. It generates the production of the nuclear factor kB (NFkB), along with pro-inflammatory cytokines like IL-1, IL-6, and TNF-α as well as serum amyloid A3 (SAA3), alpha l-acid glycoprotein, the lipocalin 24p3 and plasminogen activator inhibitor-1 (PAI-1).…”

Section: Adipose Tissue-associated Inflammationmentioning

confidence: 99%

Inflammation in Obesity-Related Complications in Children: The Protective Effect of Diet and Its Potential Role as a Therapeutic Agent

et al. 2020

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Obesity is a growing health problem in both children and adults, impairing physical and mental state and impacting health care system costs in both developed and developing countries. It is well-known that individuals with excessive weight gain frequently develop obesity-related complications, which are mainly known as Non-Communicable Diseases (NCDs), including cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, hypertension, hyperlipidemia and many other risk factors proven to be associated with chronic inflammation, causing disability and reduced life expectancy. This review aims to present and discuss complications related to inflammation in pediatric obesity, the critical role of nutrition and diet in obesity-comorbidity prevention and treatment, and the impact of lifestyle. Appropriate early dietary intervention for the management of pediatric overweight and obesity is recommended for overall healthy growth and prevention of comorbidities in adulthood.

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Section: Adipose Tissue-associated Inflammationmentioning

confidence: 99%

Inflammation in Obesity-Related Complications in Children: The Protective Effect of Diet and Its Potential Role as a Therapeutic Agent

et al. 2020

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“…It is now accepted that macrophages play important roles in the occurrence and development of AS. M1 macrophages are predominant in developing and unstable plaques, which are characterized by the secretion of pro-inflammatory cytokines and expression of M1 phenotypic marker iNOS ( 21 ). Results from our in vivo study suggested that M1 macrophages were accumulated in atherosclerotic plaques.…”

Section: Discussionmentioning

confidence: 99%

Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells

Zhang

Qiu

et al. 2021

Front. Cardiovasc. Med.

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Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels.Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact.Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.

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“…Moreover, the M2 polarization effect of ADM2 in vitro and in vivo could be at least partially reversed by a PPARγ antagonist, indicating that ADM2 might facilitate the dynamic shift from M1 to M2 under diabetic conditions through the PPARγ/IκBα/NF-κB pathway. However, various pathways participate in AGE-induced M1 macrophage polarization under DM conditions, and the comprehensive mechanisms, except for PPARγ activation, induced by ADM2 are poorly understood [37][38][39]. In addition, in order to inhibit the pathophysiological process caused by AGE/RAGE interaction, direct interventions upstream also represent a potential therapeutic strategy, including inhibition of AGE formation, downregulation of RAGE expression, and blockage of AGE/RAGE interaction [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis

Wang

Kong

Wang

et al. 2020

Preprint

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Background Both advanced glycation end products (AGEs) and AGE-mediated M1 macrophage polarization contribute to bone marrow mesenchymal stem cell (BMSC) dysfunction, leading to impaired bone regeneration in type 1 diabetes mellitus (T1DM). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and reduction of insulin resistance. However, the effects and underlying mechanisms of ADM2 in AGE-induced macrophage M1 polarization, BMSC dysfunction, and impaired bone regeneration remain poorly understood. Methods The polarization of bone marrow-derived macrophages was verified by flow cytometry analysis. In addition, alkaline phosphatase (ALP) staining, ALP activity detection, and alizarin red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence staining were used to assess polarization markers, PPARγ/IκBα/NF-κB signaling, and osteogenic markers. In vivo, a distraction osteogenesis (DO) rat model with T1DM was established, and the tibia samples were collected at different time points for radiological, biomechanical, and histological analyses, to verify the effects of ADM2 in terms of bone regeneration and M2 polarization under diabetic conditions. Results ADM2 treatment reversed the M1 macrophage polarization induced by AGEs towards the M2 phenotype, which was partially achieved by the PPARγ-mediated inhibition of NF-κB signaling. The PPARγ inhibitor GW9662 significantly attenuated the effects of ADM2. Besides, ADM2 treatment improved the AGE-impaired osteogenic potential of BMSCs in vitro. Furthermore, ADM2 accelerated bone regeneration, as revealed by improved radiological and histological manifestations and biomechanical parameters, accompanied by improved M2 macrophage polarization in diabetic DO rats, and these effects were partially blocked by GW9662 administration. Conclusions These results indicate that ADM2 enhances diabetic bone regeneration during DO, by attenuating AGE-induced imbalance in macrophage polarization, partly through PPARγ/IκBα/NF-κB signaling, and improving AGE-impaired osteogenic differentiation of BMSCs simultaneously. These findings reveal that ADM2 may serve as a potential bioactive factor for promoting bone regeneration under diabetic conditions, and imply that management of inflammation and osteogenesis, in parallel, might be a promising therapeutic strategy for diabetic patients during DO treatment.

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Toll-like receptor 4 plays a key role in advanced glycation end products-induced M1 macrophage polarization

Cited by 34 publications

References 23 publications

Inflammation in Obesity-Related Complications in Children: The Protective Effect of Diet and Its Potential Role as a Therapeutic Agent

Inflammation in Obesity-Related Complications in Children: The Protective Effect of Diet and Its Potential Role as a Therapeutic Agent

Rivaroxaban Suppresses Atherosclerosis by Inhibiting FXa-Induced Macrophage M1 Polarization-Mediated Phenotypic Conversion of Vascular Smooth Muscle Cells

Adrenomedullin 2 improves bone regeneration in type 1 diabetic rats by restoring imbalanced macrophage polarization and impaired osteogenesis

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