scholarly journals 367 Apremilast Switches Pro-Inflammatory M1 Macrophages to Anti-Inflammatory M2 Macrophages – Transcription Factors Beyond CREB

2019 ◽  
Vol 139 (9) ◽  
pp. S277
Author(s):  
R.K. Pandey ◽  
P. Maity ◽  
K. Singh ◽  
L. Krug ◽  
S. Schatz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Anti Inflammatory

scholarly journals The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease

2020 ◽  
Author(s):  
Roddy Hiram ◽  
Feng Xiong ◽  
Patrice Naud ◽  
Jiening Xiao ◽  
Martin Sirois ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
M2 Macrophages ◽  
Gene Microarray ◽  
Resolvin D1 ◽  
Right Heart ◽  
M1 Macrophages ◽  
Anti Inflammatory ◽  
Inflammation Resolution ◽  
Inflammatory Signalling

Abstract Aims Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. Methods and results Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. Conclusion The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

scholarly journals Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2

2020 ◽  
Author(s):  
Fuyu Duan ◽  
Liyan Guo ◽  
Liuliu Yang ◽  
Yuling Han ◽  
Abhimanyu Thakur ◽  
...  
Keyword(s):  
Early Stage ◽  
Synergistic Effects ◽  
Inflammatory Factors ◽  
Target Cells ◽  
Lung Cells ◽  
Alveolar Type ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Abstract Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

scholarly journals Exosome Treatment Enhances Anti-Inflammatory M2 Macrophages and Reduces Inflammation-Induced Pyroptosis in Doxorubicin-Induced Cardiomyopathy

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1224 ◽  
Author(s):  
Dinender K. Singla ◽  
Taylor A. Johnson ◽  
Zahra Tavakoli Dargani
Keyword(s):  
Cell Signaling ◽  
Cardiac Remodeling ◽  
Heart Function ◽  
Es Cells ◽  
Antineoplastic Agent ◽  
Embryonic Stem ◽  
Signaling Proteins ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Anti Inflammatory

Doxorubicin (Dox) is an effective antineoplastic agent used to treat cancers, but its use is limited as Dox induces adverse cardiotoxic effects. Dox-induced cardiotoxicity (DIC) can lead to heart failure and death. There is no study that investigates whether embryonic stem cell-derived exosomes (ES-Exos) in DIC can attenuate inflammation-induced pyroptosis, pro-inflammatory M1 macrophages, inflammatory cell signaling, and adverse cardiac remodeling. For this purpose, we transplanted ES-Exos and compared with ES-cells (ESCs) to examine pyroptosis, inflammation, cell signaling, adverse cardiac remodeling, and their influence on DIC induced cardiac dysfunction. Therefore, we used C57BL/6J mice ages 10 ± 2 weeks and divided them into four groups (n = 6–8/group): Control, Dox, Dox + ESCs, and Dox + ES-Exos. Our data shows that the Dox treatment significantly increased expression of inflammasome markers (TLR4 and NLRP3), pyroptotic markers (caspase-1, IL1-β, and IL-18), cell signaling proteins (MyD88, p-P38, and p-JNK), pro-inflammatory M1 macrophages, and TNF-α cytokine. This increased pyroptosis, inflammation, and cell signaling proteins were inhibited with ES-Exos or ESCs. Moreover, ES-Exos or ESCs increased M2 macrophages and anti-inflammatory cytokine, IL-10. Additionally, ES-Exos or ESCs treatment inhibited significantly cytoplasmic vacuolization, myofibril loss, hypertrophy, and improved heart function. In conclusion, for the first time we demonstrated that Dox-induced pyroptosis and cardiac remodeling are ameliorated by ES-Exos or ESCs.

scholarly journals Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages

2010 ◽  
Vol 299 (3) ◽  
pp. H656-H663 ◽  
Author(s):  
Fina Lovren ◽  
Yi Pan ◽  
Adrian Quan ◽  
Paul E. Szmitko ◽  
Krishna K. Singh ◽  
...  
Keyword(s):  
Visceral Obesity ◽  
Human Monocyte ◽  
Mannose Receptor ◽  
Alternative Activation ◽  
Peroxisome Proliferator ◽  
Human Monocytes ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anti Inflammatory

Altered macrophage kinetics is a pivotal mechanism of visceral obesity-induced inflammation and cardiometabolic risk. Because monocytes can differentiate into either proatherogenic M1 macrophages or anti-inflammatory M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. We hypothesized that adiponectin may prime human monocytes toward the M2 phenotype. Adiponectin promoted the alternative activation of human monocytes into anti-inflammatory M2 macrophages as opposed to the classically activated M1 phenotype. Adiponectin-treated cells displayed increased M2 markers, including the mannose receptor (MR) and alternative macrophage activation-associated CC chemokine-1. Incubation of M1 macrophages with adiponectin-treated M2-derived culture supernatant resulted in a pronounced inhibition of tumor necrosis factor-α and monocyte chemotactic protein-1 secretion. Activation of human monocytes into M2 macrophages by adiponectin was mediated, in addition to AMP-activated protein kinase and peroxisome proliferator-activated receptor (PPAR)-γ, via PPAR-α. Furthermore, macrophages isolated from adiponectin knockout mice demonstrated diminished levels of M2 markers such as MR, which were restored with adiponectin treatment. We report a novel immunoregulatory mechanism through which adiponectin primes human monocyte differentiation into anti-inflammatory M2 macrophages. Conditions associated with low adiponectin levels, such as visceral obesity and insulin resistance, may promote atherosclerosis, in part through aberrant macrophage kinetics.

scholarly journals The immunomodulatory potential of the arylmethylaminosteroid sc1o

2020 ◽  
Author(s):  
Leonard Blum ◽  
Thomas Ulshöfer ◽  
Marina Henke ◽  
Reimar Krieg ◽  
Isabell Berneburg ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Escape ◽  
Resistance Mechanisms ◽  
Host Immune System ◽  
M2 Macrophages ◽  
Steroid Compound ◽  
M1 Macrophages ◽  
Drug Candidates ◽  
Dendritic Cell Differentiation ◽  
Anti Inflammatory

Abstract Developing resistance mechanisms of pathogens against established and frequently used drugs are a growing global health problem. Besides the development of novel drug candidates per se, new approaches to counteract resistance mechanisms are needed. Drug candidates that not only target the pathogens directly but also modify the host immune system might boost anti-parasitic defence and facilitate clearance of pathogens. In this study, we investigated whether the novel anti-parasitic steroid compound 1o (sc1o), effective against the parasites Plasmodium falciparum and Schistosoma mansoni, might exhibit immunomodulatory properties. Our results reveal that 50 μM sc1o amplified the inflammatory potential of M1 macrophages and shifted M2 macrophages in a pro-inflammatory direction. Since M1 macrophages used predominantly glycolysis as an energy source, it is noteworthy that sc1o increased glycolysis and decreased oxidative phosphorylation in M2 macrophages. The effect of sc1o on the differentiation and activation of dendritic cells was ambiguous, since both pro- and anti-inflammatory markers were regulated. In conclusion, sc1o has several immunomodulatory effects that could possibly assist the immune system by counteracting the anti-inflammatory immune escape strategy of the parasite P. falciparum or by increasing pro-inflammatory mechanisms against pathogens, albeit at a higher concentration than that required for the anti-parasitic effect. Key messages • The anti-parasitic steroid compound 1o (sc1o) can modulate human immune cells. • Sc1o amplified the potential of M1 macrophages. • Sc1o shifts M2 macrophages to a M1 phenotype. • Dendritic cell differentiation and activation was ambiguously modulated. • Administration of sc1o could possibly assist the anti-parasitic defence.

scholarly journals Healing of Primary and Recurrent Mouse Ocular Herpetic Disease Following Topical Ocular Treatment with an Engineered Fibroblast Growth Factor-1 (FGF-1) is Associated with Increased Frequency and Function of Corneal Anti-Inflammatory M2 Macrophages

2020 ◽  
Author(s):  
Nisha R Dhanushkodi ◽  
Ruchi Srivastava ◽  
Pierre-Gregoire A. Coulon ◽  
Swayam Prakash ◽  
Soumyabrata Roy ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Fibroblast Growth ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Stromal Keratitis ◽  
Anti Inflammatory ◽  
Simplex Virus ◽  
M2 Phenotype ◽  
Hsv 1

ABSTRACTHerpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced primary and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited a significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.IMPORTANCEHerpes Simplex Virus type 1 (HSV-1) is a prevalent human pathogen that infects the cornea causing potentially blinding herpetic disease. The present study is the first to demonstrate a reduction of primary and recurrent corneal herpetic disease in mice following engineered FGF-1 (TTHX1114) treatment. This was associated with a decrease of pro-inflammatory M1 macrophages and an increase of anti-inflammatory M2 macrophages infiltrating the corneas of HSV-1 infected mice. The finding in mice were confirmed in humans by showing that in vitro FGF-1 treatment skewed the polarization of primary monocyte-derived macrophages into the anti-inflammatory M2 phenotype. Moreover, FGF-1 treatment appeared to reduce production of anti-inflammatory mediators. This pre-clinical finding support this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent corneal herpetic disease in the clinic.

scholarly journals Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2

2020 ◽  
Author(s):  
Fuyu Duan ◽  
Liyan Guo ◽  
Liuliu Yang ◽  
Yuling Han ◽  
Abhimanyu Thakur ◽  
...  
Keyword(s):  
Early Stage ◽  
Synergistic Effects ◽  
Inflammatory Factors ◽  
Target Cells ◽  
Lung Cells ◽  
Alveolar Type ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Abstract Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

scholarly journals The Effects of Titanium Surfaces Modified with an Antimicrobial Peptide GL13K by Silanization on Polarization, Anti-Inflammatory, and Proinflammatory Properties of Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xuxi Chen ◽  
Lin Zhou ◽  
Dong Wu ◽  
Wenxiu Huang ◽  
Yanjun Lin ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Titanium Surface ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophages ◽  
Term Survival ◽  
M1 Macrophages ◽  
Titanium Surfaces ◽  
Anti Inflammatory

The polarization of macrophages and its anti-inflammatory and proinflammatory properties play a significant role in host response after implant placement to determine the outcome of osseointegration and long-term survival. In the previous study, we immobilized an antimicrobial peptide, GL13K, onto titanium surfaces to provide immune regulation property. In the herein presented study, we aimed at investigating whether GL13K immobilized titanium surface could improve osteogenesis and reduce the inflammatory reaction around the biomaterials by altering macrophage response. We evaluated the cell proliferation of the different phenotypes of macrophages seeded in GL13K-coated titanium surface, which indicated an inhibition of M1 macrophages and a good cytocompatibility to M2 macrophages. Then, we measured the inflammatory and anti-inflammatory activity of the M1 and M2 macrophages seeded on the GL13K-coated titanium surfaces. The results of the enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction showed that the group with the GL13K modified surface had a downregulation in the expression level of the tumor necrosis factor-α and interleukin-1β in M1 macrophages and an upregulation of IL-10 and transforming growth factor-β3 (TGF-β3) levels in M2 macrophages. This study demonstrated that the GL13K modified titanium surfaces can regulate macrophages’ polarization and the expression of inflammatory and anti-inflammatory effects, reducing the effects of the inflammatory process, which may promote the process of bone regeneration and osseointegration.

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