scholarly journals Rapamycin and FTY720 Alleviate Atherosclerosis by Cross Talk of Macrophage Polarization and Autophagy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Rui-zhen Sun ◽  
Ying Fan ◽  
Xiao Liang ◽  
Tian-tian Gong ◽  
Qi Wang ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Macrophage Polarization ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
Activated Macrophage ◽  
Phenotype Markers ◽  
Alternatively Activated ◽  
Classically Activated

Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-)β, arginase 1 (Arg1), and mannose receptor C-type 1 (Mrc1) were decreased by rapamycin in peritoneal macrophages. LC3-II was also obviously enhanced, though polarization markers were unchanged in rapamycin-treated foam cells. Moreover, lipid accumulation was inhibited in rapamycin-treated macrophage cells but was unchanged in rapamycin-treated foam cells. For FTY720, LC3-II did not change, whereas TGF-β, Arg1 and Mrc1 were augmented, and IL-6 was suppressed in macrophages. However, LC3-II was increased, and TGF-β, ARG1 and MRC1 were strikingly augmented, whereas IL-6, COX2 and iNOS could be suppressed in foam cells. Furthermore, lipid accumulation was alleviated in FTY720-treated foam cells. Additionally, S1pr1 was markedly decreased in foam cells (P< .05); S1pr2, S1pr3, S1pr4 and S1pr5 were unchanged in rapamycin-treated foam cells. In FTY720-treated foam cells, S1pr3 and S1pr4 were decreased, and S1pr1, S1pr2 and S1pr5 were unchanged. Therefore, we deduced that rapamycin stimulated classically activated macrophages and supressed early atherosclerosis. Rapamycin may also stabilize artery plaques by preventing apoptosis and S1PR1 in advanced atherosclerosis. FTY720 allowed transformation of foam cells into alternatively activated macrophages through the autophagy pathway to alleviate advanced atherosclerosis.

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 Trichuris muris infection drives cell-intrinsic IL4R alpha independent colonic RELMα+ macrophages

2021 ◽  
Vol 17 (7) ◽  
pp. e1009768
Author(s):  
Ruth Forman ◽  
Larisa Logunova ◽  
Hannah Smith ◽  
Kelly Wemyss ◽  
Iris Mair ◽  
...  
Keyword(s):  
Parasitic Infection ◽  
Model Systems ◽  
Unexpected Finding ◽  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
Trichuris Muris ◽  
Alternatively Activated Macrophages ◽  
Activated Macrophage ◽  
Alternatively Activated Macrophage ◽  
Alternatively Activated

The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection.

scholarly journals Role of Macrophage Polarization in Acute Respiratory Distress Syndrome

2021 ◽  
Vol 1 (4) ◽  
pp. 260-272
Author(s):  
Priyanka Mishra ◽  
Nikhil Pandey ◽  
Ratna Pandey ◽  
Yamini B Tripathi
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Macrophage Polarization ◽  
Timely Manner ◽  
Activated Macrophage ◽  
Alternatively Activated ◽  
Classically Activated

Acute Respiratory Distress Syndrome is a familiar and destructive clinical condition characterized by progressive, swift and impaired pulmonary state. It leads to mortality if not managed in a timely manner. Recently the role of imbalanced macrophage polarization has been reported in ARDS. Macrophages are known for their heterogeneity and plasticity. Under different microenvironmental stimuli, they (M0) can switch between classically activated macrophage (M1) and alternatively activated (M2) states. This switch is regulated by several signaling pathways and epigenetic changes. In this review, the importance of macrophage M1 and M2 has been discussed in the arena of ARDS citing the phase-wise impact of macrophage polarization. This will provide a further understanding of the molecular mechanism involved in ARDS and will help in developing novel therapeutic targets. Various biomarkers that are currently used concerning this pathophysiological feature have also been summarized.

Abstract 11059: Role of Sirtuin 6 in Macrophage Polarization and Cardiac Repair in Diabetes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana S Babu ◽  
Garikipati V Srikanth ◽  
Alexander R Mackie ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Experimental Studies ◽  
Peritoneal Macrophages ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Raw 264.7 Cells ◽  
Mouse Bone Marrow ◽  
Macrophage Phenotype ◽  
Intramyocardial Injection ◽  
M2 Phenotype

Clinical and experimental studies provide evidence that metabolic and inflammatory pathways are functionally interconnected to cardiovascular diseases. Dynamic changes in macrophage activation [classical M1 activation (promote inflammation) or alternative M2 activation (promote wound healing)], in response to various stress signals, modulate cardiac physiopathology in diabetes. Sirtuin 6 (SIRT6), a NAD-dependent nuclear deacetylase plays an important role in genomic stability, cellular metabolism, stress response and aging. However, the mechanism by which SIRT6 activity affects macrophage phenotype and cardiac function in diabetes is still unexplored. Mouse bone marrow-derived macrophages (BMM) exposed to high glucose (HG, 25mM D-glucose) showed reduced expression of SIRT6 as compared to low glucose (LG, 5mM D-glucose)- and osmotic control (OC, 5mM D-glucose+20mM D-mannitol)-treated cells, associated with increased expression of proinflammatory cytokine and transcription factors (NFkb, c-JUN, FOXO, SP1 and STAT1). In addition, SIRT6 level was reduced in peritoneal macrophages of both diabetic models (streptozotocin-induced and db/db mice) as compared to non-diabetic mice. SIRT6 knockdown in RAW 264.7 cells exaggerated inflammatory response when exposed to HG. In contrast, IL-4-induced increase in mRNA expression of macrophage M2 phenotype markers like Arg1, Chi4l4, Retnla and IRS-2, but not IRS-1 expression was repressed suggesting that alternative macrophage (M2) phenotype was defective in SIRT6 deficient BM-macrophages under HG condition. SIRT6 protein expression was low in myocardial infarction-induced (MI) and diabetes-affected hearts. Interestingly, mice receiving intramyocardial injection of SIRT6-deficient macrophages showed further deterioration in left ventricular function, post-MI. Taken together, these data highlight a role for SIRT6 in regulating the balance of M1/M2 polarization, therefore, modulate macrophage mediated cardiac repair and regeneration in numerous inflammatory disease states including diabetes

scholarly journals Gaucher Cells Demonstrate a Distinct Macrophage Phenotype and Resemble Alternatively Activated Macrophages

2004 ◽  
Vol 122 (3) ◽  
pp. 359-369 ◽  
Author(s):  
Leonie A. Boven ◽  
Marjan van Meurs ◽  
Rolf G. Boot ◽  
Atul Mehta ◽  
Louis Boon ◽  
...  
Keyword(s):  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Alternatively Activated

scholarly journals IL10 Alters Peri-Collateral Macrophage Polarization and Hind-Limb Reperfusion in Mice after Femoral Artery Ligation

2020 ◽  
Vol 21 (8) ◽  
pp. 2821 ◽  
Author(s):  
Alexander M. Götze ◽  
Christian Schubert ◽  
Georg Jung ◽  
Oliver Dörr ◽  
Christoph Liebetrau ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Hind Limb ◽  
Macrophage Activation ◽  
Macrophage Polarization ◽  
Doppler Imaging ◽  
Activated Macrophages ◽  
Artery Ligation ◽  
Alternatively Activated Macrophages ◽  
Collateral Growth ◽  
Alternatively Activated

Arteriogenesis is a process by which a pre-existing arterioarterial anastomosis develops into a functional collateral network following an arterial occlusion. Alternatively activated macrophages polarized by IL10 have been described to promote collateral growth. This study investigates the effect of different levels of IL10 on hind-limb reperfusion and the distribution of perivascular macrophage activation types in mice after femoral artery ligation (FAL). IL10 and anti-IL10 were administered before FAL and the arteriogenic response was measured by Laser-Doppler-Imaging perioperatively, after 3, 7, and 14 d. Reperfusion recovery was accelerated when treated with IL10 and impaired with anti-IL10. Furthermore, symptoms of ischemia on ligated hind-limbs had the highest incidence after application of anti-IL10. Perivascular macrophages were immunohistologically phenotyped using CD163 and CD68 in adductor muscle segments. The proportion of alternatively activated macrophages (CD163+/CD68+) in relation to classically activated macrophages (CD163−/CD68+) observed was the highest when treated with IL10 and suppressed with anti-IL10. This study underlines the proarteriogenic response with increased levels of IL10 and demonstrates an in-vivo alteration of macrophage activation types in the perivascular bed of growing collaterals.

scholarly journals Similarity and Diversity in Macrophage Activation by Nematodes, Trematodes, and Cestodes

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Stephen J. Jenkins ◽  
Judith E. Allen
Keyword(s):  
Macrophage Activation ◽  
Helminth Infection ◽  
Current Knowledge ◽  
Host Tissue ◽  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Helminth Infections ◽  
Host Metabolism ◽  
Alternatively Activated

This review summarizes current knowledge of macrophages in helminth infections, with a focus not only on delineating the striking similarities in macrophage phenotype between diverse infections but also on highlighting the differences. Findings from many different labs illustrate that macrophages in helminth infection can act as anti-parasite effectors but can also act as powerful immune suppressors. The specific role for their alternative (Th2-mediated) activation in helminth killing or expulsion versus immune regulation remains to be determined. Meanwhile, the rapid growth in knowledge of alternatively activated macrophages will require an even more expansive view of their potential functions to include repair of host tissue and regulation of host metabolism.

scholarly journals MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxiao Zhu ◽  
Qiang Guo ◽  
Jing Zou ◽  
Bin Wang ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Luciferase Reporter ◽  
Mouse Lung ◽  
Interferon Regulatory Factor 1 ◽  
Macrophages Polarization ◽  
M1 Polarization ◽  
M1 Macrophage ◽  
Activated Macrophage ◽  
Alternatively Activated

Macrophages, an important type of immune cells, are generally polarized to classically activated macrophage (M1) or alternatively activated macrophage (M2) to respond to environmental stimuli. Signal transducer and activator of transcription 1 (STAT1), a very important transcription factor, can promote M1 macrophage polarization. However, the mechanisms of regulating STAT1 in macrophage polarization remain unclear. In the present study, STAT1 was markedly elevated, however, miR-19a-3p was down-regulated in interferon (IFN)-γ and lipopolysaccharide (LPS) treated RAW264.7 cells, and dual-luciferase reporter assay identified that miR-19a-3p directly targeted STAT1 by binding to its 3′UTR. Up-regulated miR-19a-3p inhibited M1 polarization by targeting STAT1/interferon regulatory factor 1 (IRF1) and vice versa in vitro. Consistently, overexpression of miR-19a-3p in LPS treated mice by systemically administering agomiR-19a-3p effectively reduced the inflammation in mouse lung tissues, and inhibited M1 macrophage polarization via suppressing STAT1/IRF1 pathway. In summary, our study confirmed that miR-19a-3p, as a direct regulator of STAT1, inhibited M1 macrophages polarization. The miR-19a-3p/STAT1/IRF1 pathway can potentially be used to design novel immunotherapy for modulating macrophage polarization.

scholarly journals Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Hui Liao ◽  
Yuanping Li ◽  
Xilan Zhang ◽  
Xiaoyun Zhao ◽  
Dan Zheng ◽  
...  
Keyword(s):  
High Glucose ◽  
Macrophage Polarization ◽  
Mannose Receptor ◽  
Raw 264.7 Cells ◽  
Protective Effects ◽  
Activated Macrophages ◽  
Podocyte Injury ◽  
Protein Expressions ◽  
Activated Macrophage

Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1β levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p<0.05). Tha 200 μg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p<0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1β levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p<0.05). The (Tha 200 μg/ml) MS group exhibited a decrease in TNF-α and IL-1β level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p<0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1β levels via its modulation on M1/M2 differentiation.

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