Caldecrin inhibits lipopolysaccharide-induced pro-inflammatory cytokines and M1 macrophage polarization through the immunoreceptor triggering receptor expressed in myeloid cells-2

2020 ◽  
Vol 523 (4) ◽  
pp. 1027-1033
Author(s):  
Kenjiro Bandow ◽  
Hiroya Hasegawa ◽  
Mineko Tomomura ◽  
Akito Tomomura
Keyword(s):  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
M1 Macrophage ◽  
Pro Inflammatory Cytokines

scholarly journals HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Yanjiao Li ◽  
Min Dong ◽  
Qing Wang ◽  
Santosh Kumar ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Myocardial Infarct ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Myocardial Infarct Size ◽  
Myocardial Repair ◽  
Stat3 Signaling ◽  
Gene Ablation ◽  
M1 Macrophage ◽  
Pro Inflammatory Cytokines

AbstractAppropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/− and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.

scholarly journals Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

2021 ◽  
Vol 12 ◽  
Author(s):  
Ágata C. Cevey ◽  
Paula D. Mascolo ◽  
Federico N. Penas ◽  
Azul V. Pieralisi ◽  
Aldana S. Sequeyra ◽  
...  
Keyword(s):  
Cell Line ◽  
Chagas Disease ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
Catalytic Subunit ◽  
M2 Macrophage ◽  
Socs3 Expression ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

scholarly journals Macrophage-associated pro-inflammatory state in human islets from obese individuals

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wei He ◽  
Ting Yuan ◽  
Kathrin Maedler
Keyword(s):  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Human Islets ◽  
Macrophage Phenotype ◽  
Inflammatory State ◽  
Obese Control ◽  
Inflammatory Macrophages ◽  
Inflammatory Macrophage ◽  
Pro Inflammatory Cytokines

AbstractObesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

Inflammation as the Common Biological Link Between Depression and Cardiovascular Diseases: Can Carnosine Exert a Protective Role?

2020 ◽  
Vol 27 (11) ◽  
pp. 1782-1800 ◽  
Author(s):  
Giuseppe Caruso ◽  
Claudia G. Fresta ◽  
Margherita Grasso ◽  
Rosa Santangelo ◽  
Giuseppe Lazzarino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Antioxidant Properties ◽  
Reactive Species ◽  
Inflammatory Status ◽  
Co Morbidity ◽  
The Common ◽  
Pro Inflammatory Cytokines

: Several epidemiological studies have clearly shown the high co-morbidity between depression and Cardiovascular Diseases (CVD). Different studies have been conducted to identify the common pathophysiological events of these diseases such as the overactivation of the hypothalamic- pituitary-adrenal axis and, most importantly, the dysregulation of immune system which causes a chronic pro-inflammatory status. The biological link between depression, inflammation, and CVD can be related to high levels of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, released by macrophages which play a central role in the pathophysiology of both depression and CVD. Pro-inflammatory cytokines interfere with many of the pathophysiological mechanisms relevant to depression by upregulating the rate-limiting enzymes in the metabolic pathway of tryptophan and altering serotonin metabolism. These cytokines also increase the risk to develop CVD, because activation of macrophages under this pro-inflammatory status is closely associated with endothelial dysfunction and oxidative stress, a preamble to atherosclerosis and atherothrombosis. : Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide which exerts a strong antiinflammatory activity on macrophages by suppressing reactive species and pro-inflammatory cytokines production and altering pro-inflammatory/anti-inflammatory macrophage polarization. This dipeptide exhibits antioxidant properties scavenging reactive species and preventing oxidative stress-induced pathologies such as CVD. : In the present review we will discuss the role of oxidative stress and chronic inflammation as common pathophysiological events both in depression and CVD and the preclinical and clinical evidence on the protective effect of carnosine in both diseases as well as the therapeutic potential of this dipeptide in depressed patients with a high co-morbidity of cardiovascular diseases.

scholarly journals Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization

2019 ◽  
Vol 12 (4) ◽  
pp. 888-896 ◽  
Author(s):  
Jia Wei ◽  
Daxing Tang ◽  
Chengjie Lu ◽  
Jin Yang ◽  
Yulei Lu ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Epithelial Cell Apoptosis ◽  
Life Threatening

AbstractNecrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.

Sa1777 Ex Vivo Activation of Triggering Receptor Expressed on Myeloid Cells 1 Enhances the Production of PRO-Inflammatory Cytokines by Inflammatory Bowel Disease Mucosa

2013 ◽  
Vol 144 (5) ◽  
pp. S-304
Author(s):  
Paolo Biancheri ◽  
Francesca Ammoscato ◽  
Antonio Di Sabatino ◽  
Renata Curciarello ◽  
Laurens Kruidenier ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Inflammatory Cytokines ◽  
Bowel Disease ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Inflammatory Bowel ◽  
Pro Inflammatory Cytokines

scholarly journals Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

2017 ◽  
Vol 474 (4) ◽  
pp. 521-537 ◽  
Author(s):  
Nicola J. Darling ◽  
Rachel Toth ◽  
J. Simon C. Arthur ◽  
Kristopher Clark
Keyword(s):  
Inflammatory Cytokines ◽  
Drug Targets ◽  
Macrophage Polarization ◽  
Macrophage Phenotype ◽  
Integral Role ◽  
Inflammatory Phenotype ◽  
Low Levels ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Pro Inflammatory Cytokines

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.

Abstract 492: Resolvin D2 Inhibits Murine Abdominal Aortic Aneurysm and Increases M2 Macrophage Differentiation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Nicolas H Pope ◽  
Morgan Salmon ◽  
Michael S Conte ◽  
Gorav Ailawadi ◽  
Gilbert R Upchurch
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Neointimal Hyperplasia ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Cytokine Analysis ◽  
Abdominal Aortic ◽  
Pro Inflammatory Cytokines

Objectives: Macrophages are critical to abdominal aortic aneurysm (AAA) formation; however, the role of anti-inflammatory M2 macrophages is not known. Resolvins have been shown to play a protective role in neointimal hyperplasia; however, their role in AAA has not been established. We hypothesized that treatment with Resolvin D2 (RvD2) attenuates murine AAA formation through alterations in macrophage polarization and cytokine expression. Methods: Male C57/B6 mice (n=9/group) of 8-12 weeks of age received RvD2 (100 ng/kg/treatment) or vehicle only every third day beginning three days prior to abdominal aortic perfusion with elastase. Aortas were harvested 14 days following elastase perfusion. Cytokine analysis (n=5/group) or confocal microscopy (n=4/group) was performed. Cytokine profiles were analyzed using a murine antibody array. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages (Mac2), M1 (MCP-1) and M2 (Arg-1) macrophage subtypes, α-actin and 4',6-diamidino-2-phenylindole (DAPI) was utilized. Results: Mean aortic dilation was 96.23 % (± 13.07 %) for vehicle treated and 56.58% (± 9.69%) for RvD2 treated mice (p<0.0001). Pro-inflammatory cytokines CXCL-10, IL-1β, TIMP-1 and MCP-1 were significantly elevated in control as compared to RvD2 treated animals. Confocal histology demonstrated a prevalence of M2 macrophages within the aortic media in mice treated with RvD2 (Figure 1). Conclusions: Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important pro-inflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.

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.

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