Immunoblockade of PSGL-1 attenuates established experimental murine colitis by reduction of leukocyte rolling

2004 ◽  
Vol 287 (1) ◽  
pp. G115-G124 ◽  
Author(s):  
Emile M. Rijcken ◽  
Mike G. Laukoetter ◽  
Christoph Anthoni ◽  
Stephanie Meier ◽  
Rudolf Mennigen ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Activity Index ◽  
Leukocyte Adhesion ◽  
Combined Treatment ◽  
Disease Activity Index ◽  
Leukocyte Recruitment ◽  
Leukocyte Rolling ◽  
Chronic Colitis ◽  
Adhesive Interactions

Recruitment of circulating leukocytes into the colonic tissue is a key feature of intestinal inflammation. P-selectin glycoprotein ligand-1 (PSGL-1) and very late antigen-4 (VLA-4) are expressed on leukocytes and play an important role in leukocyte-endothelial cell adhesive interactions. We examined the effects of immunoneutralization of PSGL-1 and VLA-4 on leukocyte recruitment in vivo in the development and treatment of experimental colitis. Chronic colitis was induced in balb/c mice by oral administration of dextran sodium sulfate (DSS). Monoclonal antibodies 2PH1 (anti-PSGL-1) and PS/2 (anti-VLA-4) or the combination of both were injected intravenously, and leukocyte adhesion was observed for 60 min in colonic submucosal venules by intravital microscopy (IVM) under isoflurane/N2O anesthesia. In addition, mice with established colitis were treated by daily intraperitoneal injections of 2PH1, PS/2, or the combination of both over 5 days. Disease activity index (DAI), histology, and myeloperoxidase (MPO) levels were compared with sham-treated DSS controls. We found that 2PH1 reduced the number of rolling leukocytes (148.7 ± 29.8 vs. 36.9 ± 8.7/0.01 mm2/30 s, P < 0.05), whereas leukocyte velocity was increased (24.0 ± 3.6 vs. 127.8 ± 11.7 μm/s, P < 0.05). PS/2 reduced leukocyte rolling to a lesser extent. Leukocyte firm adhesion was not influenced by 2PH1 but was strongly reduced by PS/2 (24.1 ± 2 vs. 4.4 ± 0.9/0.01 mm2/30 s, P < 0.05). Combined application did not cause additional effects on leukocyte adhesion. Treatment of chronic colitis with 2PH1 or PS/2 reduced DAI, mucosal injury, and MPO levels significantly. Combined treatment led to a significantly better reduction of DAI (0.4 ± 0.1 vs. 2.1 ± 0.2 points) and histology (9.7 ± 0.9 vs. 21.4 ± 4.6 points). In conclusion, PSGL-1 and VLA-4 play an important role for leukocyte recruitment during intestinal inflammation. Therapeutic strategies designed to disrupt interactions mediated by PSGL-1 and/or VLA-4 may prove beneficial in treatment of chronic colitis.

scholarly journals The CD200 Regulates Inflammation in Mice Independently of TNF-α Production

2021 ◽  
Vol 22 (10) ◽  
pp. 5358
Author(s):  
Katarzyna Tonecka ◽  
Agata Braniewska ◽  
Zofia Pilch ◽  
Zuzanna Sas ◽  
Marcin Skorzynski ◽  
...  
Keyword(s):  
Immune Cells ◽  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Histological Evaluation ◽  
Bodyweight Loss ◽  
Colon Tissue ◽  
Tnf Α

Inflammatory bowel disease is characterized by the infiltration of immune cells and chronic inflammation. The immune inhibitory receptor, CD200R, is involved in the downregulation of the activation of immune cells to prevent excessive inflammation. We aimed to define the role of CD200R ligand-CD200 in the experimental model of intestinal inflammation in conventionally-reared mice. Mice were given a dextran sodium sulfate solution in drinking water. Bodyweight loss was monitored daily and the disease activity index was calculated, and a histological evaluation of the colon was performed. TNF-α production was measured in the culture of small fragments of the distal colon or bone marrow-derived macrophages (BMDMs) cocultured with CD200+ cells. We found that Cd200−/− mice displayed diminished severity of colitis when compared to WT mice. Inflammation significantly diminished CD200 expression in WT mice, particularly on vascular endothelial cells and immune cells. The co-culture of BMDMs with CD200+ cells inhibited TNF-α secretion. In vivo, acute colitis induced by DSS significantly increased TNF-α secretion in colon tissue in comparison to untreated controls. However, Cd200−/− mice secreted a similar level of TNF-α to WT mice in vivo. CD200 regulates the severity of DSS-induced colitis in conventionally-reared mice. The presence of CD200+ cells decreases TNF-α production by macrophages in vitro. However, during DDS-induced intestinal inflammation secretion of TNF-α is independent of CD200 expression.

scholarly journals Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Noam Jacob ◽  
Kotaro Kumagai ◽  
Jay P. Abraham ◽  
Yosuke Shimodaira ◽  
Yuefang Ye ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Activity Index ◽  
Death Receptor ◽  
Disease Activity Index ◽  
Cell Types ◽  
Clinical Disease ◽  
Major Pathway ◽  
Intestinal Fibrosis

Abstract Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn’s disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag−/− , Rag−/− mice lacking DR3 in all cell types (Rag−/−Dr3−/−), or Rag−/− mice lacking DR3 only on fibroblasts (Rag−/−Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag−/− mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag−/−Dr3−/− demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag−/−, Rag−/−Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.

scholarly journals The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo.

1996 ◽  
Vol 183 (5) ◽  
pp. 1995-2006 ◽  
Author(s):  
B Johnston ◽  
T B Issekutz ◽  
P Kubes
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Mononuclear Cells ◽  
Leukocyte Adhesion ◽  
Systemic Vasculitis ◽  
Significant Proportion ◽  
Leukocyte Rolling ◽  
Peripheral Blood Mononuclear ◽  
Beta 2 ◽  
Adhesive Interactions

A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.

Herbal Medicine and Acupuncture Combined Treatment Attenuates Colitis in Rats

2021 ◽  
pp. 1-18
Author(s):  
Yu-Mi Lee ◽  
Seung-Ho Seo ◽  
Seong-Young Cho ◽  
Dong-Hee Choi ◽  
Min-Woo Cheon ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Acupuncture Treatment ◽  
Activity Index ◽  
Combined Treatment ◽  
Group Analysis ◽  
Microbial Control ◽  
Body Weight Loss ◽  
Disease Activity Index ◽  
Simultaneous Treatment ◽  
Treatment Groups

This study aimed to verify the efficacy of a combined treatment of Jakyakgamcho-tang (JGT) and acupuncture (CV12, ST25, CV4) on colitis induced by dextrane sulfate sodium (DSS). Changes in immuno-mediated factors and metabolites were investigated. Colitis symptoms such as body weight loss and elevated disease activity index were alleviated by the combined treatment. Moreover, treatment with JGT and acupuncture restored the disturbed architecture of colon by suppressing inflammatory cytokine levels of IFN-[Formula: see text] ([Formula: see text]), IL-5 ([Formula: see text]), and IL-13 ([Formula: see text]) compared with the DSS group. Analysis of metabolic profiles of serum revealed that treatment groups were clearly separated from the DSS group, suggesting that JGT and acupuncture treatment altered serum metabolites. Furthermore, treatments caused opposite metabolite patterns for dimethylbenzimidazole, 1,5-anhydro-D-glucitol, proline, phosphate, glycolic acid, aspartic acid, tryptophan, phthalic acid, ornithine, and glutamic acid compared with the DSS group. The combined treatment group induced more effective metabolite patterns than the JGT group, implying that acupuncture treatment can restore metabolic changes caused by DSS induction. These results indicate that the simultaneous treatment of JGT administration and acupuncture procedure provides better management of the immune function and inflammatory expression of colitis than a single treatment. It is assumed that intestinal microbial control can be achieved by acupuncture stimulation as well as by taking herbal medicine.

scholarly journals Isolation and Characterization of Potentially Probiotic Bacterial Strains from Mice: Proof of Concept for Personalized Probiotics

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1684 ◽  
Author(s):  
Larissa Celiberto ◽  
Roseli Pinto ◽  
Elizeu Rossi ◽  
Bruce Vallance ◽  
Daniela Cavallini
Keyword(s):  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Bacterial Strains ◽  
Dss Colitis ◽  
Isolation And Characterization ◽  
Inflammatory Bowel ◽  
Commercial Probiotics ◽  
Lower Disease Activity

Modulation of the gut microbiota through the use of probiotics has been widely used to treat or prevent several intestinal diseases. However, inconsistent results have compromised the efficacy of this approach, especially in severe conditions such as inflammatory bowel disease (IBD). The purpose of our study was to develop a personalized probiotic strategy and assess its efficacy in a murine model of intestinal inflammation. Commensal bacterial strains were isolated from the feces of healthy mice and then administered back to the host as a personalized treatment in dextran sodium sulfate (DSS)-induced colitis. Colonic tissues were collected for histological analysis and to investigate inflammatory markers such as Il-1β, Il-6, TGF-β, and Il-10, and the enzyme myeloperoxidase as a neutrophil marker. The group that received the personalized probiotic showed reduced susceptibility to DSS-colitis as compared to a commercial probiotic. This protection was characterized by a lower disease activity index and reduced histopathological damage in the colon. Moreover, the personalized probiotic was more effective in modulating the host immune response, leading to decreased Il-1β and Il-6 and increased TGF-β and Il-10 expression. In conclusion, our study suggests that personalized probiotics may possess an advantage over commercial probiotics in treating dysbiotic-related conditions, possibly because they are derived directly from the host’s own microbiota.

scholarly journals l-Isoleucine Administration Alleviates DSS-Induced Colitis by Regulating TLR4/MyD88/NF-κB Pathway in Rats

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiangbing Mao ◽  
Rui Sun ◽  
Qingxiang Wang ◽  
Daiwen Chen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Activity Index ◽  
Control Diet ◽  
Average Daily Gain ◽  
Disease Activity Index ◽  
Inflammatory Cells ◽  
Feed Conversion ◽  
Enterocyte Apoptosis

Inflammatory bowel disease (namely, colitis) severely impairs human health. Isoleucine is reported to regulate immune function (such as the production of immunoreactive substances). The aim of this study was to investigate whether l-isoleucine administration might alleviate dextran sulfate sodium (DSS)-induced colitis in rats. In the in vitro trial, IEC-18 cells were treated by 4 mmol/L l-isoleucine for 12 h, which relieved the decrease of cell viability that was induced by TNF-α (10 ng/ml) challenge for 24 h (P &lt;0.05). Then, in the in vivo experiment, a total of 44 Wistar rats were allotted into 2 groups that were fed l-isoleucine-supplemented diet and control diet for 35 d. From 15 to 35 d, half of the rats in the 2 groups drank the 4% DSS-adding water. Average daily gain, average daily feed intake and feed conversion of rats were impaired by DSS challenge (P &lt;0.05). Drinking the DSS-supplementing water also increased disease activity index (DAI) and serum urea nitrogen level (P &lt;0.05), shortened colonic length (P &lt;0.05), impaired colonic enterocyte apoptosis, cell cycle, and the ZO-1 mRNA expression (P &lt;0.05), increased the ratio of CD11c-, CD64-, and CD169-positive cells in colon (P &lt;0.05), and induced extensive ulcer, infiltration of inflammatory cells, and collagenous fiber hyperplasia in colon. However, dietary l-isoleucine supplementation attenuated the negative effect of DSS challenge on growth performance (P &lt;0.05), DAI (P &lt;0.05), colonic length and enterocyte apoptosis (P &lt;0.05), and dysfunction of colonic histology, and downregulated the ratio of CD11c-, CD64-, and CD169-positive cells, pro-inflammation cytokines and the mRNA expression of TLR4, MyD88, and NF-κB in the colon of rats (P &lt;0.05). These results suggest that supplementing l-isoleucine in diet improved the DSS-induced growth stunting and colonic damage in rats, which could be associated with the downregulation of inflammation via regulating TLR4/MyD88/NF-κB pathway in colon.

The Adipokine Metrnl Ameliorates Chronic Colitis in Il-10–/– Mice by Attenuating Mesenteric Adipose Tissue Lesions During Spontaneous Colitis

2019 ◽  
Vol 13 (7) ◽  
pp. 931-941 ◽  
Author(s):  
Lugen Zuo ◽  
Sitang Ge ◽  
Yuanyuan Ge ◽  
Jingjing Li ◽  
Bing Zhu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Colitis ◽  
Protective Effects ◽  
Systemic Delivery ◽  
Chronic Colitis ◽  
Mesenteric Adipose Tissue ◽  
Proinflammatory Mediators ◽  
Ppar Γ

Abstract Background Crosstalk between mesenteric adipose tissue [MAT] and the intestines affects the progression of Crohn’s disease [CD]. The adipokine metrnl regulates adipocyte function and has anti-inflammatory activity. We aimed to explore metrnl expression in CD MAT, investigate the influence of metrnl on the experimental colitis disease course and determine the mechanism underlying this effect. Methods Metrnl expression in MAT specimens obtained from patients with and without CD was tested by immunohistochemistry. Male Il-10–/– mice with spontaneous enteritis were divided into positive control and metrnl-treated [Metrnl-Fc, 10 mg/kg/d, intraperitoneally, 8 weeks] groups. Age-matched male wild-type [WT] mice were used as negative controls. The effects of metrnl on enteritis and mesenteric lesions and the potential controlling mechanisms were evaluated. Results Metrnl expression was higher in human CD MAT than in control MAT. Systemic delivery of metrnl significantly ameliorated chronic colitis in Il-10–/– mice, as demonstrated by decreases in the disease activity index, inflammatory score and proinflammatory mediators. The protective effects of metrnl on MAT included reduced mesenteric hypertrophy, increased adipocyte size, improved adipocyte intrinsic function and ameliorated inflammation. Metrnl treatment activated STAT5/PPAR-γ signaling and promoted adipocyte differentiation in the MAT. Conclusions Metrnl expression was increased in the MAT of CD patients. Metrnl administration attenuated mesenteric lesions by promoting adipocyte function and differentiation partly through STAT5/PPAR-γ signaling pathway activation, thereby ameliorating CD-like colitis in mice.

Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis

2001 ◽  
Vol 280 (2) ◽  
pp. G291-G297 ◽  
Author(s):  
Cameron W. Lush ◽  
Gediminas Cepinskas ◽  
William J. Sibbald ◽  
Peter R. Kvietys
Keyword(s):  
Leukocyte Adhesion ◽  
Cecal Ligation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Endothelial Adhesion Molecule ◽  
Acute Peritonitis ◽  
Leukocyte Accumulation ◽  
Deficient Mice

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)−/− mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS−/− and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS−/− mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS−/− mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS−/− mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS−/− mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.

Leukocyte adhesion in local versus hemorrhage-induced ischemia

1992 ◽  
Vol 263 (3) ◽  
pp. H810-H815 ◽  
Author(s):  
M. A. Perry ◽  
D. N. Granger
Keyword(s):  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Leukocyte Rolling ◽  
Leukocyte Adherence ◽  
Rolling Velocity ◽  
Local Ischemia ◽  
Cell Adhesive ◽  
Local Restriction ◽  
Adhesive Interactions

The objective of this study was to compare the leukocyte-endothelial cell adhesive interactions elicited in postcapillary venules by either local ischemia-reperfusion or hemorrhage-reperfusion. Leukocyte rolling, adherence, and emigration were monitored in cat mesenteric venules exposed to an 85% reduction in blood flow (induced by either hemorrhage or local restriction of arterial inflow) for 1 h, followed by 1 h reperfusion. Leukocyte-endothelial cell interactions, venular diameter, and red blood cell velocity were measured during baseline, ischemia, and reperfusion periods. Both local and hemorrhage-induced ischemia reperfusion caused a reduction in leukocyte rolling velocity and increases in leukocyte adherence and emigration. Quantitatively, the adherence and emigration responses in both ischemia models were nearly identical. However, the two models differed in their response to immunoneutralization of the leukocyte adhesion glycoprotein CD11/CD18 with monoclonal antibody (MAb) IB4. The MAb had a more profound effect in attenuating leukocyte adherence and emigration in the local ischemia model. These results indicate that different factors may contribute to leukocyte-endothelial cell adhesive interactions observed in local vs. systemic models of ischemia-reperfusion.

scholarly journals In Vivo Imaging of Leukocyte Recruitment to the Atheroprone Femoral Artery Reveals Anti-Inflammatory Effects of Rosuvastatin

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Mizuko Osaka ◽  
Sumihiko Hagita ◽  
Masayuki Yoshida
Keyword(s):  
Oxidative Stress ◽  
Femoral Artery ◽  
Leukocyte Adhesion ◽  
Underlying Mechanism ◽  
Leukocyte Recruitment ◽  
Hmg Coa Reductase Inhibitor ◽  
Anti Inflammatory ◽  
Coa Reductase ◽  
Inflammatory Effect

Objective. To monitor the anti-inflammatory effect of rosuvastatin in leukocyte endothelial interactions in the atheroprone femoral artery in vivo.Methods and Results. Male Apolipoprotein E null mice (ApoE−/− mice, 6 weeks old) were fed a high-fat diet (20% fat, 1.25% cholesterol) with or without the HMG CoA reductase inhibitor rosuvastatin (10 mg/kg/day) for 6 weeks. Significant leukocyte adhesion was observed in the femoral artery of ApoE−/− mice, but not of wild type mice, in the absence of rosuvastatin. Interestingly, no obvious plaque formation was observed in the artery at this time point. The number of adherent leukocytes was dramatically diminished in ApoE−/− mice treated with rosuvastatin. DHE-associated oxidative stress and the expression of gp91-phox, a component of NADPH oxidase, were induced in ApoE−/− mice and were abolished by rosuvastatin treatment.Conclusion. Our data documented leukocyte recruitment prior to lipid accumulation and subsequent inhibition by rosuvastatin. The underlying mechanism seemed to involve oxidative stress and an anti-inflammatory effect on the endothelium of atheroprone vessels.

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