scholarly journals Astragaloside IV Alleviates the Experimental DSS-Induced Colitis by Remodeling Macrophage Polarization Through STAT Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Lianlian Tian ◽  
Jun-Long Zhao ◽  
Jian-Qin Kang ◽  
Shi-bo Guo ◽  
Nini Zhang ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Macrophage Polarization ◽  
Experimental Colitis ◽  
Clinical Activity ◽  
Macrophage Phenotype ◽  
Astragaloside Iv ◽  
Stat Signaling ◽  
Inflammatory Macrophages

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicine. Some previous studies indicated that Astragaloside IV (AS-IV), a natural saponin extracted from the traditional Chinese medicine herb Ligusticum chuanxiong, alleviates the experimental colitis symptoms in vitro and in vivo. However, the mechanism of AS-IV on IBD remains unclear. Accumulating evidence suggests that M2-polarized intestinal macrophages play a pivotal role in IBD progression. Here, we found that AS-IV attenuated clinical activity of DSS-induced colitis that mimics human IBD and resulted in the phenotypic transition of macrophages from immature pro-inflammatory macrophages to mature pro-resolving macrophages. In vitro, the phenotype changes of macrophages were observed by qRT-PCR after bone marrow-derived macrophages (BMDMs) were induced to M1/M2 and incubated with AS-IV, respectively. In addition, AS-IV was effective in inhibiting pro-inflammatory macrophages and promoting the pro-resolving macrophages to ameliorate experimental colitis via the regulation of the STAT signaling pathway. Hence, we propose that AS-IV can ameliorate experimental colitis partially by modulating macrophage phenotype by remodeling the STAT signaling, which seems to have an essential function in the ability of AS-IV to alleviate the pathological progress of IBD.

scholarly journals RETRACTED ARTICLE:Deficiency in intestinal epithelial Reg4 ameliorates intestinal inflammation and alters the colonic bacterial composition

2019 ◽  
Vol 12 (4) ◽  
pp. 919-929 ◽  
Author(s):  
Yongtao Xiao ◽  
Ying Lu ◽  
Ying Wang ◽  
Weihui Yan ◽  
Wei Cai
Keyword(s):  
Intestinal Inflammation ◽  
Elevated Serum ◽  
Intestinal Failure ◽  
Experimental Colitis ◽  
Mucosal Injury ◽  
Intestinal Epithelial ◽  
Bacterial Composition ◽  
Novel Target

AbstractThe regenerating islet-derived family member 4 (Reg4) in the gastrointestinal tract is up-regulated during intestinal inflammation. However, the physiological function of Reg4 in the inflammation is largely unknown. In the current study, the functional roles and involved mechanisms of intestinal epithelial Reg4 in intestinal inflammation were studied in healthy and inflamed states using human intestinal specimens, an intestinal conditional Reg4 knockout mouse (Reg4ΔIEC) model and dextran sulfate sodium (DSS)-induced colitis model. We showed that the elevated serum Reg4 in pediatric intestinal failure (IF) patients were positively correlated with the serum concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In inflamed intestine of IF patients, the crypt base Reg4 protein was increased and highly expressed towards the luminal face. The Reg4 was indicated as a novel target of activating transcription factor 2 (ATF2) that enhanced Reg4 expression during the intestinal inflammation. In vivo, the DSS-induced colitis was significantly ameliorated in Reg4ΔIEC mice. Reg4ΔIEC mice altered the colonic bacterial composition and reduced the bacteria adhere to the colonic epithelium. In vitro, Reg4 was showed to promote the growth of colonic organoids, and that this occurs through a mechanism involving activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, our findings demonstrated intestinal-epithelial Reg4 deficiency protects against experimental colitis and mucosal injury via a mechanism involving alteration of bacterial homeostasis and STAT3 activation.

scholarly journals Lactobacillus paracaseiReduces Intestinal Inflammation in Adoptive Transfer Mouse Model of Experimental Colitis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Manuel Oliveira ◽  
Nabil Bosco ◽  
Genevieve Perruisseau ◽  
Jeanne Nicolas ◽  
Iris Segura-Roggero ◽  
...  
Keyword(s):  
Mouse Model ◽  
Adoptive Transfer ◽  
Immune Modulation ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Lactobacillus Paracasei ◽  
Therapeutic Benefits

Studies showed that specific probiotics provide therapeutic benefits in inflammatory bowel disease.In vitroevidence suggested thatLactobacillus paracaseialso called ST11 (CNCM I-2116) is a potent strain with immune modulation properties. However, little is known about its capacity to alleviate inflammatory symptomsin vivoIn this context, the main objective of this study was to investigate the role of ST11 on intestinal inflammation using the adoptive transfer mouse model of experimental colitis. Rag2-/-recipient mice were fed with ST11 (109CFU/day)a month prior toinduce colitis by adoptive transfer of naive T cells. One month later, in clear contrast to nonfed mice, weight loss was significantly reduced by 50% in ST11-fed mice. Further analysis of colon specimens revealed a significant reduction neutrophil infiltration and mucosal expression of IL1β, IL-6, and IL12 proinflammatory cytokines, whereas no consistent differences in expression of antibacterial peptides or tight junction proteins were observed between PBS and ST11-fed mice. All together, our results demonstrate that oral administration of ST11 was safe and had a significant preventive effect on colitis. We conclude that probiotics such asLactobacillus paracaseiharbor worthwhilein vivoimmunomodulatory properties to prevent intestinal inflammation by nutritional approaches.

scholarly journals Somatostatin does not attenuate intestinal injury in dextran sodium sulphate-induced subacute colitis

1998 ◽  
Vol 7 (3) ◽  
pp. 169-173 ◽  
Author(s):  
J. D. van Bergeijk ◽  
M. E. van Meeteren ◽  
C. J. A. M. Tak ◽  
A. P. M. van Dijk ◽  
M. A. C. Meijssen ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Sodium Sulphate ◽  
Dextran Sodium Sulphate ◽  
Acute Colitis ◽  
Inflammatory Score ◽  
Long Acting ◽  
Intestinal Macrophage

From severalin vitroandin vivostudies involvement of som atostatin (SMS) in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 μg daily) or octreotide (3 μg daily) subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS) 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin1 β (IL-1 β), IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.

scholarly journals Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Paulo José Basso ◽  
Helioswilton Sales-Campos ◽  
Viviani Nardini ◽  
Murillo Duarte-Silva ◽  
Vanessa Beatriz Freitas Alves ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Predictive Biomarker ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Anti Inflammatory

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara-/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

scholarly journals Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Qiang Li ◽  
Xiaoxiao Fu ◽  
Jiang Yuan ◽  
Shu Han
Keyword(s):  
T Regulatory Cells ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Endothelial Permeability ◽  
M2 Macrophage ◽  
Vascular Endothelial ◽  
Macrophage Phenotype ◽  
Thrombospondin 1

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of “anti-inflammatory” T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

scholarly journals Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Li ◽  
Suzette Riddle ◽  
Sushil Kumar ◽  
Joanna Poczobutt ◽  
B. Alexandre McKeon ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Macrophage Polarization ◽  
Pulmonary Arteries ◽  
Cell Types ◽  
Metabolic Reprogramming ◽  
Macrophage Phenotype ◽  
Inflammatory Monocytes ◽  
Adventitial Fibroblasts

The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.

scholarly journals Expression of Cav1.3 calcium channel in the human and mouse colon: posttranscriptional inhibition by IFNγ

2017 ◽  
Vol 312 (1) ◽  
pp. G77-G84 ◽  
Author(s):  
Vijayababu M. Radhakrishnan ◽  
Maryam M. Gilpatrick ◽  
Nour Alhoda Parsa ◽  
Pawel R. Kiela ◽  
Fayez K. Ghishan
Keyword(s):  
Transcriptional Repression ◽  
Intestinal Inflammation ◽  
Gene Promoter ◽  
Experimental Colitis ◽  
Trinitrobenzene Sulfonic Acid ◽  
Mineral Density ◽  
Altered Expression ◽  
Relative Contribution

It has been hypothesized that apically expressed L-type Ca2+channel Cav1.3 (encoded by CACNA1D gene) contributes toward an alternative TRPV6-independent route of intestinal epithelial Ca2+absorption, especially during digestion when high luminal concentration of Ca2+and other nutrients limit TRPV6 contribution. We and others have implicated altered expression and activity of key mediators of intestinal and renal Ca2+(re)absorption as contributors to negative systemic Ca2+balance and bone loss in intestinal inflammation. Here, we investigated the effects of experimental colitis and related inflammatory mediators on colonic Cav1.3 expression. We confirmed Cav1.3 expression within the segments of the mouse and human gastrointestinal tract. Consistent with available microarray data (GEO database) from inflammatory bowel disease (IBD) patients, mouse colonic expression of Cav1.3 was significantly reduced in trinitrobenzene sulfonic acid (TNBS) colitis. In vitro, IFNγ most potently reduced Cav1.3 expression. We reproduced these findings in vivo with wild-type and Stat1−/−mice injected with IFNγ. The observed effect in Stat1−/−suggested a noncanonical transcriptional repression or a posttranscriptional mechanism. In support of the latter, we observed no effect on the cloned Cav1.3 gene promoter activity and accelerated Cav1.3 mRNA decay rate in IFNγ-treated HCT116 cells. While the relative contribution of Cav1.3 to intestinal Ca2+absorption and its value as a therapeutic target remain to be established, we postulate that Cav1.3 downregulation in IBD may contribute to the negative systemic Ca2+balance, to increased bone resorption, and to reduced bone mineral density in IBD patients.

scholarly journals Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease

2020 ◽  
Vol 51 (11) ◽  
pp. 891-902
Author(s):  
Jason E. Engel ◽  
Maxx L. Williams ◽  
Erika Williams ◽  
Camille Azar ◽  
Erin B. Taylor ◽  
...  
Keyword(s):  
Renal Function ◽  
Multidetector Ct ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Macrophage Phenotype ◽  
Renovascular Disease ◽  
Targeting Peptide ◽  
And Function ◽  
Inflammatory Macrophages

<b><i>Background:</i></b> Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. <b><i>Methods:</i></b> Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). <b><i>Results:</i></b> Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. <b><i>Conclusions:</i></b> Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

scholarly journals Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ying Zhang ◽  
Conghui Zhang ◽  
Lixi Li ◽  
Xinjun Liang ◽  
Peng Cheng ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Macrophage Polarization ◽  
Lymphatic Vessels ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Close Relationship ◽  
Stage Renal Disease

AbstractInflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

scholarly journals Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 211
Author(s):  
Sona Kauerova ◽  
Hana Bartuskova ◽  
Barbora Muffova ◽  
Libor Janousek ◽  
Jiri Fronek ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ldl Cholesterol ◽  
Macrophage Polarization ◽  
Inflammatory Activity ◽  
Human Macrophage ◽  
Macrophage Phenotype ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages ◽  
Inflammatory Macrophage

Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism.

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