scholarly journals Lysophosphatidylcholine acyltransferase 2 (LPCAT2) Regulates The Expression of Macrophage Phenotype Markers in RAW264.7 Cells.

2021 ◽  
Author(s):  
Victory Ibigo Poloamina ◽  
Hanaa Alrammah ◽  
Wondwossen Abate ◽  
Gyorgy Fejer ◽  
Simon K Jackson
Keyword(s):  
Inflammatory Responses ◽  
Lipid Mediator ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Phenotype Markers ◽  
Antigen Presenting ◽  
Oxide Synthase ◽  
First Time ◽  
Inducible Nitric Oxide

Macrophages are key antigen-presenting cells that also secrete cytokines during inflammation. They can be polarised to M1 or M2 phenotypes. Molecules such as CD206 and inducible Nitric Oxide Synthase are considered macrophage phenotype markers because they are highly expressed in either M1 or M2 macrophages. LPCAT2 is a lipid mediator that influences inflammatory responses in macrophages. However, how LPCAT2 influences inflammation is not fully understood. In this study, we have used genetic technology to study the influence of LPCAT2 on macrophage phenotype markers. Our results show for the first time that overexpression of LPCAT2 promotes the expression of M1 macrophage phenotype markers, and attenuates the expression of M2 macrophage markers.

scholarly journals Role of microRNA-21 and Its Underlying Mechanisms in Inflammatory Responses in Diabetic Wounds

2020 ◽  
Vol 21 (9) ◽  
pp. 3328 ◽  
Author(s):  
Cole Liechty ◽  
Junyi Hu ◽  
Liping Zhang ◽  
Kenneth W. Liechty ◽  
Junwang Xu
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Regulation Of Gene Expression ◽  
Mouse Skin ◽  
M2 Macrophage ◽  
Central Feature ◽  
Macrophage Phenotype ◽  
Macrophage Cells ◽  
M1 Macrophage ◽  
Diabetic Wounds

A central feature of diabetic wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of pro-inflammatory (M1) macrophages in diabetic wounds. Persistence of the M1 macrophage phenotype and failure to transition to the regenerative or pro-remodeling (M2) macrophage phenotype plays an indispensable role in diabetic wound impairment; however, the mechanism underlying this relationship remains unclear. Recently, microRNAs have been shown to provide an additional layer of regulation of gene expression. In particular, microRNA-21 (miR-21) is essential for an inflammatory immune response. We hypothesize that miR-21 plays a role in regulating inflammation by promoting M1 macrophage polarization and the production of reactive oxygen species (ROS). To test our hypothesis, we employed an in vivo mouse skin wound model in conjunction with an in vitro mouse model to assess miR-21 expression and macrophage polarization. First, we found that miR-21 exhibits a distinct expression pattern in each phase of healing in diabetic wounds. MiR-21 abundance was higher during early and late phases of wound repair in diabetic wounds, while it was significantly lower in the middle phase of wounding (at days 3 and 7 following wounding). In macrophage cells, M1 polarized macrophages exhibited an upregulation of miR-21, as well as the M1 and pro-inflammatory markers IL-1b, TNFa, iNos, IL-6, and IL-8. Overexpression of miR-21 in macrophage cells resulted in an upregulation of miR-21 and also increased expression of the M1 markers IL-1b, TNFa, iNos, and IL-6. Furthermore, hyperglycemia induced NOX2 expression and ROS production through the HG/miR-21/PI3K/NOX2/ROS signaling cascade. These findings provide evidence that miR-21 is involved in the regulation of inflammation. Dysregulation of miR-21 may explain the abnormal inflammation and persistent M1 macrophage polarization seen in diabetic wounds.

scholarly journals Transcriptome profiling reveals new insights into the roles of neuronal nitric oxide synthase on macrophage polarization towards classically activated phenotype

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257908
Author(s):  
Pingan Chang ◽  
Hao Gao ◽  
Quan Sun ◽  
Xiaohong He ◽  
Feifei Huang
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
Macrophage Polarization ◽  
Neuronal Nitric Oxide Synthase ◽  
M2 Macrophage ◽  
M1 Macrophage ◽  
M2 Macrophage Polarization ◽  
Oxide Synthase ◽  
First Time ◽  
Classically Activated

In response to various stimuli, naïve macrophages usually polarize to M1 (classically activated) or M2 (alternatively activated) cells with distinct biological functions. Neuronal nitric oxide synthase (NOS1) is involved in M1 macrophage polarization at an early stage. Here, we show for the first time that NOS1 is dispensable for M2 macrophage polarization for the first time. Further, differentially expressed genes (DEGs) regulated by NOS1 signaling in M1-polarized macrophages stimulated with lipopolysaccharide (LPS) were characterized by transcriptome analysis of wild-type (WT) and NOS1 knockout mouse macrophages. Thousands of affected genes were detected 2 h post LPS challenge, and this wide-ranging effect became greater with a longer stimulation time (8 h post LPS). NOS1 deficiency caused dysregulated expression of hundreds of LPS-responsive genes. Most DEGs were enriched in biological processes related to transcription and regulation of the immune and inflammatory response. At 2 h post-LPS, the toll-like receptor (TLR) signaling pathway, cytokine–cytokine receptor interaction, and NOD-like receptor signaling pathway were the major pathways affected, whereas the main pathways affected at 8 h post-LPS were Th1 and Th2 cell differentiation, FoxO, and AMPK signaling pathway. Identified DEGs were validated by real-time quantitative PCR and interacted in a complicated signaling pathway network. Collectively, our data show that NOS1 is dispensable for M2 macrophage polarization and reveal novel insights in the role of NOS1 signaling at different stages of M1 macrophage polarization through distinct TLR4 plasma membrane-localized and endosome-internalized signaling pathways.

Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes

2014 ◽  
Vol 92 (7) ◽  
pp. 575-582 ◽  
Author(s):  
Lee Winchester ◽  
Sudhakar Veeranki ◽  
Srikanth Givvimani ◽  
Suresh C. Tyagi
Keyword(s):  
Skeletal Muscle ◽  
Gaba Receptors ◽  
M2 Macrophage ◽  
Regular Exercise ◽  
Peroxisome Proliferator ◽  
Macrophage Phenotype ◽  
Peroxisome Proliferator Activated Receptor ◽  
M1 Macrophage ◽  
Inflammatory Profile ◽  
White Fat

Regular exercise is a great medicine with its benefits encompassing everything from prevention of cardiovascular risk to alleviation of different muscular myopathies. Interestingly, elevated levels of homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy), antagonizes beta-2 adrenergic receptors (β2AR), gamma amino butyric acid (GABA), and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors. HHcy also stimulates an elevation of the M1/M2 macrophage ratio, resulting in a more inflammatory profile. In this review we discuss several potential targets altered by HHcy that result in myopathy and excessive fat accumulation. Several of these HHcy mediated changes can be countered by exercise and culminate into mitigation of HHcy induced myopathy and metabolic syndrome. We suggest that exercise directly impacts levels of Hcy, matrix metalloproteinase 9 (MMP-9), macrophages, and G-protein coupled receptors (GPCRs, especially Gs). While HHcy promotes the M1 macrophage phenotype, it appears that exercise may diminish the M1/M2 ratio, resulting in a less inflammatory phenotype. HHcy through its influence on GPCRs, specifically β2AR, PPARγ and GABA receptors, promotes accumulation of white fat, whereas exercise enhances the browning of white fat and counters HHcy-mediated effects on GPCRs. Alleviation of HHcy-associated pathologies with exercise also includes reversal of excessive MMP-9 activation. Moreover, exercise, by reducing plasma Hcy levels, may prevent skeletal muscle myopathy, improve exercise capacity and rescue the obese phenotype. The purpose of this review is to summarize the pathological conditions surrounding HHcy and to clarify the importance of regular exercise as a method of disease prevention.

scholarly journals Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aβ42through Nrf2-Related Inflammatory Response

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Ji Yeon Seo ◽  
Euisun Pyo ◽  
Jin-Pyo An ◽  
Jinwoong Kim ◽  
Sang Hyun Sung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Microglial Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Antioxidant Response ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Ht22 Cells ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Therapeutic approach of Alzheimer’s disease (AD) has been gradually diversified. We examined the therapeutic and preventive potential of andrographolide, which is a lactone diterpenoid fromAndrographis paniculata, and focused on the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated heme oxygenase (HO)-1-inducing effects and the inhibitory activity of amyloid beta (Aβ)42-induced microglial activation related to Nrf2 and nuclear factorκB (NF-κB)-mediated inflammatory responses. Andrographolide induced the expression and translocation of Nrf2 from the cytoplasm to the nucleus, thereby activating antioxidant response element (ARE) gene transcription and HO-1 expression in murine hippocampal HT22 cells. Andrographolide eliminated intracellular Aβ42in BV-2 cells and decreased the production of interleukin (IL)-6, IL-1β, prostaglandin (PG)E2, and nitric oxide (NO) because of artificial phagocytic Aβ42. It decreased pNF-κB accumulation in the nucleus and the expression of inducible nitric oxide synthase (i-NOS) and cyclooxygenase II (COX-II) in the microglial BV-2 cell line. In summary, andrographolide activates Nrf2-mediated HO-1 expression and inhibits Aβ42-overexpressed microglial BV-2 cell activation. These results suggested that andrographolide might have the potential for further examination of the therapeutics of AD.

scholarly journals AR Deficiency Inhibits LPS-induced M1 Response in Macrophages by Activating Autophagy

2020 ◽  
Author(s):  
Peng Cheng ◽  
Jianwei Xie ◽  
Zhiyong Liu ◽  
Jian Wang
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Oxide Synthase

Abstract Macrophage M1 polarization mediates inflammatory responses and tissue damage. Recently, aldose reductase (AR) has been shown to play a critical role in of M1 polarization in macrophages. However, the underlying mechanisms are unknown. Here, we demonstrated, for the first time, that AR deficiency repressed the induction of inducible nitric oxide synthase in lipopolysaccharide (LPS)-stimulated macrophages via activation of autophagy. This suppression was related to a defect in the inhibitor of nuclear factor κB (NF-κB) kinase (IKK) complex in the classical NF-κB pathway. However, the mRNA levels of the IKKβ and IKKγ were not reduced in LPS-treated AR knockout (KO) macrophages, indicating that their proteins were downregulated at the post-transcriptional level. We discovered that LPS stimuli induced the recruitment of more beclin1 and increased autophagosome formation in AR-deficient macrophages. Blocking autophagy by 3-methyladenine and ammonium chloride treatment restored IKKβ and IKKγ protein levels and increased nitric oxide synthase production in LPS-stimulated AR-deficient macrophages. More assembled IKKβ and IKKγ undergo ubiquitination and recruit the autophagic adaptor p62 in LPS-induced AR KO macrophages, promoting their delivery to autophagosomes and lysosomes. Collectively, these findings suggest that AR deficiency involves in the regulation of NF-κB signaling, and extends the role of selective autophagy in fine-tuned M1 macrophage polarization.

scholarly journals Targeted delivery of miR-99b reprograms tumor-associated macrophage phenotype leading to tumor regression

2020 ◽  
Vol 8 (2) ◽  
pp. e000517
Author(s):  
Liang Wang ◽  
Yi-Yang Hu ◽  
Jun-Long Zhao ◽  
Fei Huang ◽  
Shi-Qian Liang ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Western Blot ◽  
Antigen Presentation ◽  
Targeted Delivery ◽  
Tunel Staining ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Qrt Pcr ◽  
M1 Macrophage ◽  
Potential Strategy

BackgroundAccumulating evidence has shown that tumor-associated macrophages (TAMs) play a critical role in tumor progression. Targeting TAMs is a potential strategy for tumor immunotherapy. However, the mechanism underlying the TAM phenotype and function needs to be resolved. Our previous studies have demonstrated that miR-125a can reverse the TAM phenotype toward antitumor. Meanwhile, we have found that miR-125a and miR-99b cluster in the first intron of the same host gene, and are transcribed simultaneously in bone marrow-derived macrophages (BMDMs) following LPS+IFNγ stimulation. However, it remains unclear whether miR-99b by itself can exert an antitumor effect by regulating macrophage phenotype.MethodsmiR-99b and/or miR-125a were delivered into TAMs of orthotopic hepatocellular carcinoma (HCC) or subcutaneous Lewis lung cancer (LLC) mice. The effect of treatment was evaluated by live imaging, TUNEL staining and survival tests. The phenotype of the immune cells was determined by qRT-PCR, ELISA, western blot and FACS. The capability of miR-99b-mediated macrophage phagocytosis and antigen presentation was detected by FACS and immunofluorescence staining. The underlying molecular mechanism was examined by qRT-PCR, reporter assay and western blot, and further verified in the tumor model. The expression of miR-99b and its target genes was determined in TAMs sorted from tumor and adjacent tissues in patients with liver cancer.ResultsTargeted delivery of miR-99b and/or miR-125a into TAMs significantly impeded the growth of HCC and LLC, especially after miR-99b delivery. More importantly, the delivery of miR-99b re-educated TAM toward antitumor phenotype with enhanced immune surveillance. Further investigation of mechanisms showed that macrophage-specific overexpression of miR-99b promoted M1 while suppressing M2 macrophage polarization by targeting κB-Ras2 and/or mTOR, respectively. miR-99b-overexpressed M1 macrophage was characterized by stronger capability of phagocytosis and antigen presentation. Additionally, delivery of simTOR or siκB-Ras2 into TAMs inhibited miR-99b antagomir-triggered tumor growth. Finally, miR-99b expression was lower in TAMs of patients with liver cancer than that in adjacent tissues, while the expression of κB-Ras2 and mTOR was reversed.ConclusionsOur results reveal the mechanism of miR-99b-mediated TAM phenotype, indicating that TAM-targeted delivery of miR-99b is a potential strategy for cancer immunotherapy.

scholarly journals EZH1 Is Associated with TCP-Induced Bone Regeneration through Macrophage Polarization

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaoshi Jia ◽  
Hudi Xu ◽  
Richard J. Miron ◽  
Chengcheng Yin ◽  
Xiaoxin Zhang ◽  
...  
Keyword(s):  
Bone Repair ◽  
Macrophage Polarization ◽  
Repair Process ◽  
Potential Interaction ◽  
Target System ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Gene Target ◽  
M2 Macrophage Polarization ◽  
Antigen Presenting

Macrophages have been found to regulate the effects of biomaterials throughout the entire tissue repair process as an antigen-presenting cell. As a well-defined osteoconductive biomaterial for bone defect regeneration, tricalcium phosphate (TCP) has been found to facilitate a favourable osteoimmunomodulatory response that can shift macrophage polarization towards the M2 phenotype. In the present study, our group discovered that a histone methyltransferase enhancer of zeste1 (EZH1) was drastically downregulated in Thp1 cells stimulated by TCP, indicating that EZH1 may participate in the macrophage phenotype shifting. Furthermore, the NF-κB pathway in macrophages was significantly downregulated through stimulation of TCP, suggesting a potential interaction between EZH1 and the NF-κB pathway. Utilizing gene knock-down therapy in macrophages, it was found that depletion of EZH1 induced M2 macrophage polarization but did not downregulate NF-κB. When the NF-κB pathway was inhibited, the expression of EZH1 was significantly downregulated, suggesting that the inhibition of EZH1 may be regulated by the NF-κB pathway. These novel findings provide valuable insights into a potential gene target system that controls M2 macrophage polarization which ultimately favours a microenvironment suitable for bone repair.

scholarly journals Hyperoxia Exacerbates Postnatal Inflammation-Induced Lung Injury in Neonatal BRP-39 Null Mutant Mice Promoting the M1 Macrophage Phenotype

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Mansoor A. Syed ◽  
Vineet Bhandari
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Continuous Exposure ◽  
Macrophage Phenotype ◽  
Cell Counts ◽  
M1 Macrophage ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Anti Inflammatory

Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages.Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury.Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. Forin vivostudies, wild-type (WT) and BRP-39−/−mice received continuous exposure to 21% O2(control mice) or 100% O2from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed.Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39−/−mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice.Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury.

scholarly journals Induction of Heme Oxygenase-1 with Hemin Reduces Obesity-Induced Adipose Tissue Inflammation via Adipose Macrophage Phenotype Switching

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Thai Hien Tu ◽  
Yeonsoo Joe ◽  
Hye-Seon Choi ◽  
Hun Taeg Chung ◽  
Rina Yu
Keyword(s):  
Heme Oxygenase ◽  
Marker Genes ◽  
Heme Oxygenase 1 ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Phenotype Switching ◽  
Anti Inflammatory ◽  
Adipose Inflammation ◽  
M2 Phenotype

Adipose macrophages with the anti-inflammatory M2 phenotype protect against obesity-induced inflammation and insulin resistance. Heme oxygenase-1 (HO-1), which elicits antioxidant and anti-inflammatory activity, modulates macrophage phenotypes and thus is implicated in various inflammatory diseases. Here, we demonstrate that the HO-1 inducer, hemin, protects against obesity-induced adipose inflammation by inducing macrophages to switch to the M2 phenotype. HO-1 induction by hemin reduced the production of proinflammatory cytokines (TNF-αand IL-6) from cocultured adipocytes and macrophages by inhibiting the activation of inflammatory signaling molecules (JNK and NF-κB) in both cell types. Hemin enhanced transcript levels of M2 macrophage marker genes (IL-4, Mrc1, and Clec10a) in the cocultures, while reducing transcripts of M1 macrophage markers (CD274 and TNF-α). The protective effects of hemin on adipose inflammation and macrophage phenotype switching were confirmed in mice fed a high-fat diet, and these were associated with PPARγupregulation and STAT6 activation. These findings suggest that induction of HO-1 with hemin protects against obesity-induced adipose inflammation through M2 macrophage phenotype switching, which is induced by the PPARγand STAT6 pathway. HO-1 inducers such as hemin may be useful for preventing obesity-induced adipose inflammation.

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