scholarly journals Role of interplay between IL-4 and IFN-γ in the in regulating M1 macrophage polarization induced by Nattectin

2012 ◽  
Vol 14 (4) ◽  
pp. 513-522 ◽  
Author(s):  
Edson Kiyotaka Ishizuka ◽  
Marcio José Ferreira ◽  
Lidiane Zito Grund ◽  
Erica Maria Martins Coutinho ◽  
Evilin Naname Komegae ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
M1 Macrophage ◽  
Ifn Γ

scholarly journals POS0333 ALTERED MACROPHAGE POLARIZATION PHENOTYPES IN SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 394.1-394
Author(s):  
A. Hukara ◽  
M. Rudnik ◽  
C. B. Rufer ◽  
O. Distler ◽  
P. Blyszczuk ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Macrophage Polarization ◽  
Peritoneal Macrophages ◽  
Surface Marker ◽  
Surface Marker Expression ◽  
Tnf Α ◽  
Ifn Γ ◽  
Alternatively Activated ◽  
Classically Activated

Background:Fos-like 2 (Fosl-2) is a transcription factor of the AP-1 family and has a broad range in inducing cellular changes affecting fibrosis and inflammatory responses. Pathological effects of Fosl-2 have been associated with systemic sclerosis (SSc). In addition, increased expression of Fosl-2 has been detected in human SSc monocyte-derived macrophages [1]. Monocytes and macrophages play a central role in activating and propagating acute inflammation followed by pathological fibrosis and organ dysfunction. The classification of the macrophage polarization phenotype can be assigned based on the stimulus, for example into classically-activated M(LPS), and alternatively-activated M(IL-4) macrophages [2]. However, the role of the Fosl-2 transcription factor in macrophage polarization remains elusive.Objectives:To investigate the role of Fosl-2 in macrophage polarization in SSc using Fosl-2 overexpressing transgenic (Fosl-2 tg) mice and human blood-derived macrophages from SSc patients.Methods:Thiogylcolate-elicited peritoneal macrophages were isolated from wild-type (wt) and Fosl-2 tg mice. Human peripheral CD14+ blood-derived monocytes were isolated and differentiated to macrophages (hMDM) from healthy controls and SSc patients. Murine and human macrophages were polarized with LPS (10 ng/ml), LPS + recombinant mouse IFN-γ (10 ng/ml), recombinant mouse, resp. human IL-4 (10 ng/ml) or remained untreated. Macrophage surface marker expression was assessed by flow cytometry using a mouse (F4/80, CD11b, CD86, CD80, CD38, MHCII, CD206, PD-L1, PD-L2, CD36) or human (CD38, CD40, CD86, PD-L2, PD-L1, CD163, CD206) designed polarization panel. Phagocytic activity was detected with pHrodo Red E.coli particles by flow cytometry. Gene expression and secretion of pro- and anti-inflammatory markers were measured by RT-qPCR, standard ELISAs and Griess Assay for nitric oxide production.Results:After LPS stimulation, mRNA levels of IL-1β (p<0.01, n=11-12), TNF-α (p=0.05, n=11-12) and IFN-γ (p<0.05, n=7) were reduced, whereas expression of IL-10 (p<0.05, n=11-12) was enhanced in Fosl-2 tg peritoneal macrophages in comparison to wt cells. Secretion of TNF-α (p<0.01, n=9-11) and nitric oxide (p<0.01, n=9) was impaired in Fosl-2 tg peritoneal macrophages compared to wt cells after LPS stimulation. Peritoneal macrophages were analyzed directly after isolation for macrophage polarization cell surface marker expression. Fosl-2 tg peritoneal macrophages showed an increase in the F4/80+CD11b+PD-L2+CD36+ cell population (p<0.01, n=3-6) compared to peritoneal macrophages from wt mice.The expression of cell surface markers of non-polarized and IL-4 stimulated SSc hMDM (n=17) showed an increased percentage of CD40+CD86+CD206+PD-L2+CD163+ cells (p<0.05) compared to healthy control hMDM (n=7). Phagocytic activity was enhanced in SSc hMDM (n=7) compared to healthy untreated (p<0.05), LPS (p=0.05) and IL-4 (p<0.05) hMDM (n=5).Conclusion:Our animal data indicates a role of Fosl-2 in regulating macrophage polarization with a shift from a classically-activated to an alternatively-activated phenotype. Similarly, SSc hMDM resemble a functional M(IL-4) alternative macrophage phenotype.Thus, maintaining a balanced proportion of classically- and alternatively-activated macrophage phenotypes may be an effective tool to control macrophage function in SSc.References:[1]Moreno-Moral, A., et al., Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk. Ann Rheum Dis, 2018. 77(4): p. 596-601.[2]Kania, G., M. Rudnik, and O. Distler, Involvement of the myeloid cell compartment in fibrogenesis and systemic sclerosis. Nat Rev Rheumatol, 2019. 15(5): p. 288-302.Disclosure of Interests:Amela Hukara: None declared, Michal Rudnik: None declared, Chantal Brigitta Rufer: None declared, Oliver Distler Speakers bureau: Actelion, Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche, Menarini, Mepha, MSD, iQone, Pfizer, Consultant of: Abbvie, Actelion, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, ChemomAb, Corpuspharma, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Kymera, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi, UCB, Lilly, Target BioScience, Pfizer, Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, Kymera Therapeutics, Mitsubishi Tanabe, Przemyslaw Blyszczuk: None declared, Gabriela Kania: None declared

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.

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

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 501-515 ◽  
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.

scholarly journals SIRT6 inhibition delays peripheral nerve recovery by suppressing migration, phagocytosis and M2-polarization of macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Zou ◽  
Jiaqi Zhang ◽  
Jiawei Xu ◽  
Lanya Fu ◽  
Yizhou Xu ◽  
...  
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Macrophage Polarization ◽  
Nerve Degeneration ◽  
M2 Polarization ◽  
M1 Macrophage ◽  
Nerve Recovery

Abstract Background Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Prior evidences suggested that the anti-inflammatory function of SIRT6 after spinal cord and brain injury, and it plays a crucial role in macrophages polarization of adipose tissue and skin. However, the role of SIRT6 in macrophages involved peripheral nerve injury is still unknown. Given the prominent role of macrophages in peripheral nerve recovery, we aim to investigate the role of SIRT6 in the regulation of phenotypes shift and functions in macrophages after peripheral nerve injury. Results In the present study, we first identified a significant increase of SIRT6 expression during nerve degeneration and macrophages phagocytosis. Next, we found nerve recovery was delayed after SIRT6 silencing by injected shRNA lentivirus into the crushed sciatic nerve, which exhibited a reduced expression of myelin-related proteins (e.g., MAG and MBP), severer myoatrophy of target muscles, and inferior nerve conduction compared to the shRNA control injected mice. In vitro, we found that SIRT6 inhibition by being treated with a selective inhibitor OSS_128167 or lentivirus transfection impairs migration and phagocytosis capacity of bone marrow-derived macrophages (BMDM). In addition, SIRT6 expression was discovered to be reduced after M1 polarization, but SIRT6 was enhanced after M2 polarization in the monocyte-macrophage cell line RAW264.7 and BMDM. Moreover, SIRT6 inhibition increased M1 macrophage polarization with a concomitant decrease in M2 polarization both in RAW264.7 and BMDM via activating NF-κB and TNF-α expression, and SIRT6 activation by UBCS039 treatment could shift the macrophages from M1 to M2 phenotype. Conclusion Our findings indicate that SIRT6 inhibition impairs peripheral nerve repair through suppressing the migration, phagocytosis, and M2 polarization of macrophages. Therefore, SIRT6 may become a favorable therapeutic target for peripheral nerve injury.

scholarly journals MiR-520a-3p Inhibited Macrophage Polarization and Promoted the Development of Atherosclerosis via Targeting UVRAG in Apolipoprotein E Knockout Mice

2021 ◽  
Vol 7 ◽  
Author(s):  
Jing Rui Qi ◽  
Dian Ru Zhao ◽  
Li Zhao ◽  
Fan Luo ◽  
Mei Yang
Keyword(s):  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Treatment Target ◽  
Vessel Disease ◽  
Novel Treatment ◽  
M1 Macrophage ◽  
Apolipoprotein E Knockout Mice ◽  
The World ◽  
M2 Macrophage Polarization

Atherosclerosis (AS), a kind of chronic inflammatory blood vessel disease, is a main cause of cardiovascular disease, which is a leading cause of mortality around the world. Accumulation of macrophages induced by inflammation contributes to AS development. It has been indicated that microRNAs (miRNAs) are involved in the process of AS. However, the pathway and gene miRNAs targeting are poorly understood. Here we reported that miR-520a-3p was increased in mice with AS and silencing of miR-520a-3p attenuated AS process. Furthermore, inhibition of miR-520a-3p increased the expression of α-SMA and collagen. In addition, miR-520a-3p silencing inhibited the expression of M1 macrophage polarization markers and pro-inflammatory genes and promoted the M2 macrophage polarization. What’s more, forced expression of miR-520a-3p diminished IL4/IL13 induced macrophage autophagy via targeting UVRAG. Collectively, our study reveals the role of miR-520a-3p in macrophage polarization and suggests the potential of miRNA as a novel treatment target of AS.

scholarly journals TET1 Knockdown Inhibits Porphyromonas gingivalis LPS/IFN-γ-Induced M1 Macrophage Polarization through the NF-κB Pathway in THP-1 Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 2023 ◽  
Author(s):  
Huang ◽  
Tian ◽  
Li ◽  
Xu
Keyword(s):  
Porphyromonas Gingivalis ◽  
Periodontal Diseases ◽  
Macrophage Polarization ◽  
Control Group ◽  
M1 Macrophages ◽  
Expression Levels ◽  
Hla Dr ◽  
M1 Macrophage ◽  
Significant Difference ◽  
Ifn Γ

Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.

scholarly journals Aspartate Metabolism Facilitates IL-1β Production in Inflammatory Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Wang ◽  
Xueyue Zheng ◽  
Bingnan Liu ◽  
Yaoyao Xia ◽  
Zhongquan Xin ◽  
...  
Keyword(s):  
Immune Cells ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Hypoxia Inducible Factor ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Ifn Γ ◽  
Inflammatory Macrophages

Increasing evidence support that cellular amino acid metabolism shapes the fate of immune cells; however, whether aspartate metabolism dictates macrophage function is still enigmatic. Here, we found that the metabolites in aspartate metabolism are depleted in lipopolysaccharide (LPS) plus interferon gamma (IFN-γ)-stimulated macrophages. Aspartate promotes interleukin-1β (IL-1β) secretion in M1 macrophages. Mechanistically, aspartate boosts the activation of hypoxia-inducible factor-1α (HIF-1α) and inflammasome and increases the levels of metabolites in aspartate metabolism, such as asparagine. Interestingly, asparagine also accelerates the activation of cellular signaling pathways and promotes the production of inflammatory cytokines from macrophages. Moreover, aspartate supplementation augments the macrophage-mediated inflammatory responses in mice and piglets. These results uncover a previously uncharacterized role for aspartate metabolism in directing M1 macrophage polarization.

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

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.

Sign in / Sign up

Export Citation Format

Share Document