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 Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 938
Author(s):  
Yi-Hsuan Lin ◽  
Yi-Hsun Wang ◽  
Yi-Jen Peng ◽  
Feng-Cheng Liu ◽  
Gu-Jiun Lin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
Macrophage Differentiation ◽  
Macrophage Cells ◽  
M1 Macrophage ◽  
Interleukin 26

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

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 Electronic Cigarette Exposure Enhances Lung Inflammatory and Fibrotic Responses in COPD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongwei Han ◽  
Guangda Peng ◽  
Maureen Meister ◽  
Hongwei Yao ◽  
Jenny J. Yang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Electronic Cigarettes ◽  
Macrophage Polarization ◽  
Electronic Cigarette ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Mucus Production ◽  
Copd Patients ◽  
Tgf Β1 ◽  
Sirius Red

Although a few studies show that the use of electronic nicotine delivery systems (ENDS) may ameliorate objective and subjective outcomes in COPD smokers who switched to electronic cigarettes, it is unclear whether e-cigarette exposure alters lung pathological features and inflammatory response in COPD. Here, we employed βENaC-overexpressing mice bearing COPD-like pulmonary abnormality, and exposed them to ENDS. We found that ENDS exposure aggravated airspace enlargement and mucus production in βENaC-overexpressing mice, which was associated with increased MMP12 and Muc5ac, respectively. ENDS exposure to mice significantly increased the numbers of macrophages, particularly in M2 macrophages in bronchoalveolar lavage (BAL) fluid, despite ENDS did not induce M2 macrophage polarization in a cultured murine macrophage cell line (RAW264.7). There were no changes in neutrophils in BAL fluid by ENDS exposure. Multiple cytokine productions were increased including M-CSF, IL-1rα, IL-10, and TGF-β1, in BAL fluid from mice when exposed to ENDS. The Sirius Red staining and hydroxyproline assay showed ENDS-exposed mice displayed enhanced fibrotic phenotypes compared to control mice. In conclusion, ENDS exposure enhances airspace enlargement, mucus secretion, and fibrogenesis in COPD mice. This is associated with increased MMP12, inflammatory responses, and M2 macrophage phenotype. This study provides pre-clinical data implicating that electronic cigarette exposure is not safe in COPD patients who want to replace traditional cigarettes with ENDS.

Abstract 19: Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Cameron McAlpine ◽  
Aric Huang ◽  
Abby Emdin ◽  
Nicole Banko ◽  
Daniel Beriault ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Atherosclerotic Lesion ◽  
M2 Macrophage ◽  
Lesion Volume ◽  
Macrophage Phenotype ◽  
Expression Of Genes ◽  
M1 Macrophage ◽  
Deficient Mice

Objective: Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diseases including diabetes, cancer, Alzheimer’s and atherosclerosis. The tissue and homolog specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell specific deletion of GSK3α or GSK3β on atherosclerosis in LDLR-/- mice. Approach and results: We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR-/- mice and mice were fed a high fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not GSK3β, reduced atherosclerotic lesion volume as well as lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α deficient mice, but not GSK3β deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization. Mechanistically, GSK3α regulated macrophage polarization by modulating the phosphorylation and activation of STAT transcription factors. Conclusions: Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by regulating STAT activation and promoting an M2 macrophage phenotype.

Abstract 17035: Inhibition of DNMT and HDAC6 Together Regulates Macrophage Polarization by FoxO1-HIF2α Signaling and Protects Endotoxemia-Induced Inflammation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Saheli Samanta ◽  
Zhigang Zhou ◽  
Sheeja Rajasingh ◽  
Kyley K Burkey ◽  
Rajasingh Johnson
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Combined Treatment ◽  
Cell Polarization ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Therapeutic Drugs ◽  
Protein Expressions ◽  
Anti Inflammatory

Introduction: Acute lung injury (ALI) is a common pulmonary disease caused by bacterial infection leading to an imbalance between pro-inflammatory and anti-inflammatory immune responses. Studies have shown that macrophage polarization (M1 and M2) during ALI plays a key role in regulating these responses. Hypothesis: We hypothesized that combined treatment with 5-Aza 2-deoxycytidine (Aza) + tubastatin A (TBA) would reduce inflammation and promote an anti-inflammatory M2 macrophage phenotype by regulating the HIF2α signaling pathway. Methods: To show the effect of Aza+TBA, lipopolysaccharide (LPS)-induced macrophages (RAW 264.7) were treated with either Aza (50nM), TBA n(750nM), or together (Aza+TBA) for 24 hours. The mRNA and protein expressions of FoxO1, HIF2α, NOS2 (M1), and CD206 (M2) were measured by qRT-PCR and Western analyses in lung tissue and macrophages. Results: Our results revealed that LPS induced macrophages showed an increased expression of NOS2 (M1) and decreased expression of Fizz-1 (M2) whereas the LPS-induced macrophages were treated with Aza+TBA showed decreased NOS2 (Fig. A) and increased Fizz-1 mRNA (Fig. B) and protein expressions. Furthermore, the LPS significantly decreased the mRNA and protein expressions of FoxO1 and HIF2α in macrophages. These expressions were significantly increased when the LPS-induced macrophages were treated with Aza +TBA (Fig. C) . These results suggest that Aza+TBA treatment together generates more M2 macrophages there by reducing the LPS-induced inflammatory responses. Conclusions: Overall, these data show the first time that the combinatorial treatment with Aza+TBA regulates macrophage cell polarization and abrogates LPS-induced inflammation through FoxO1-HIF2α signaling pathway. Thus, epigenetic modifiers may be potential therapeutic drugs for ALI. <!--EndFragment-->

scholarly journals Neutrophil-derived extracellular vesicles: proinflammatory trails and anti-inflammatory microvesicles

2019 ◽  
Author(s):  
Young-Jin Youn ◽  
Sanjeeb Shrestha ◽  
Jun-Kyu Kim ◽  
Yu-Bin Lee ◽  
Jee Hyun Lee ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Pi3k Pathway ◽  
M2 Macrophage ◽  
List Type ◽  
Protective Effects ◽  
M1 Macrophage ◽  
M2 Macrophage Polarization ◽  
Anti Inflammatory

SUMMARYExtracellular vesicles (EVs) are membrane-derived vesicles that mediate intercellular communications. Neutrophils produce different subtypes of EVs during inflammatory responses. Neutrophil-derived trails (NDTRs) are generated by neutrophils migrating toward inflammatory foci, whereas neutrophil-derived microvesicles (NDMVs) are thought to be generated by neutrophils that have arrived at the inflammatory foci. However, the physical and functional characteristics of neutrophil-derived EVs are incompletely understood. In this study, we investigated the similarities and differences between neutrophil-derived EV subtypes. Neutrophil-derived EVs shared similar characteristics regarding stimulators, generation mechanisms, and surface marker expression. Both neutrophil-derived EV subtypes exhibited similar functions, such as direct bactericidal activity and induction of monocyte chemotaxis via MCP-1. However, NDTR generation was dependent on the integrin signaling, while NDMV generation was dependent on the PI3K pathway. The CD16 expression level differentiated the neutrophil-derived EV subtypes. Interestingly, both subtypes showed different patterns of miRNA expression and were easily phagocytosed by monocytes. NDTRs induced M1 macrophage polarization, whereas NDMVs induced M2 macrophage polarization. Moreover, NDTRs but not NDMVs exerted protective effects against sepsis-induced lethality in a murine sepsis model and pathological changes in a murine chronic colitis model. These results suggest a new insight into neutrophil-derived EV subtypes: proinflammatory NDTRs and anti-inflammatory NDMVs.Key pointsNeutrophil-derived trails are proinflammatory extracellular vesicles that induce M1 macrophage polarization and protect against inflammationNeutrophil-derived microvesicles are anti-inflammatory extracellular vesicles that induce M2 macrophage polarization

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 PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wen-Lin Cheng ◽  
Quan Zhang ◽  
Bo Li ◽  
Jian-Lei Cao ◽  
Lin Jiao ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
M1 Macrophage ◽  
Pparγ Expression

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

scholarly journals Amniotic Epithelial Cells Accelerate Diabetic Wound Healing by Modulating Inflammation and Promoting Neovascularization

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yongjun Zheng ◽  
Shiqing Zheng ◽  
Xiaoming Fan ◽  
Li Li ◽  
Yongqiang Xiao ◽  
...  
Keyword(s):  
Wound Healing ◽  
Epithelial Cells ◽  
Therapeutic Potential ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Diabetic Wound ◽  
Macrophage Phenotype ◽  
Amniotic Epithelial Cells ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Human amniotic epithelial cells (hAECs) are nontumorigenic, highly abundant, and low immunogenic and possess multipotent differentiation ability, which make them become ideal alternative stem cell source for regenerative medicine. Previous studies have demonstrated the therapeutic potential of hAECs in many tissue repairs. However, the therapeutic effect of hAECs on diabetic wound healing is still unknown. In this study, we injected hAECs intradermally around the full-thickness excisional skin wounds of db/db mice and found that hAECs significantly accelerated diabetic wound healing and granulation tissue formation. To explore the underlying mechanisms, we measured inflammation and neovascularization in diabetic wounds. hAECs could modulate macrophage phenotype toward M2 macrophage, promote switch from proinflammatory status to prohealing status of wounds, and increase capillary density in diabetic wounds. Furthermore, we found that the hAEC-conditioned medium promoted macrophage polarization toward M2 phenotype and facilitated migration, proliferation, and tube formation of endothelial cells through in vitro experiments. Taken together, we first reported that hAECs could promote diabetic wound healing, at least partially, through paracrine effects to regulate inflammation and promote neovascularization.

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

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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