| 11. |
- Göranzon, C., et al.
(författare)
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Immunohistochemical characterization of lymphocytes in microscopic colitis
- 2013
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Ingår i: Journal of Crohn's and Colitis. - : Elsevier. - 1197-4982 .- 1873-9946. ; 7:10, s. e434-e442
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis (MC), encompassing the subgroups collagenous colitis (CC) and lymphocytic colitis (LC), is characterized by macroscopically normal or near-normal colonic mucosa, and an increased number of intraepithelial lymphocytes (IELs) and mononuclear cell infiltration in the underlying lamina propria (LP), in addition to an increased collagen layer in CC. This study aimed to characterize the inflammatory cells involved in mucosal inflammation, using immunohistochemistry.Methods Paraffin-embedded biopsies from 23 untreated patients with MC (CC = 13, LC = 10) and 17 controls were stained with antibodies against CD3, CD4, CD8, CD20, CD30, Foxp3, CD45RO and Ki67. Computerized image analysis was used to calculate areas of stained lymphocytes in the surface and crypt epithelia as well as in the LP.Results In CC and LC, an increase of predominantly CD8+ lymphocytes was seen in both the epithelium and the lamina propria, whereas a decreased amount of CD4+ lymphocytes was found in the lamina propria. CD45RO+ and Foxp3+ cells were more abundant in all areas in both patient groups compared to controls, as were CD20+ areas, although more scarce. Ki67+ areas were only more abundant in the epithelium, whereas CD30+ areas were more abundant in the lamina propria of both patient groups compared to controls.Conclusions This study confirms an increased amount of CD8+ lymphocytes in the epithelium. Lymphocytic proliferation and activation markers were more abundant, whereas a decreased amount of CD4+ lymphocytes was seen in the LP. Further studies are needed to reveal the underlying mechanism(s).
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| 12. |
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| 13. |
- Götlind, Yu-Yuan Chiu, 1964, et al.
(författare)
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Interplay between Th1 and Th17 effector T cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the Gai2-deficient mouse
- 2013
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Ingår i: International Immunology. - Oxford, United Kingdom : Oxford University Press. - 0953-8178 .- 1460-2377. ; 25:1, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.
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| 14. |
- Hayderi, Assim, 1990-, et al.
(författare)
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Function of viperin in human aortic SMCS and its relevance for atherosclerosis
- 2021
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Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 331, s. E88-E88
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: During atherosclerosis, activated vascular cells secrete chemokines to recruit leukocytes to the subendothelial space. Activated leukocytes, in particular activated T lymphocytes express IFN-γ, which affects the expression of numerous genes, including the antiviral protein viperin, in vascular cells. Viperin is expressed in endothelial cells of human carotid plaques but its relevance for vascular physiology and/or pathophysiology has not been established (Olofsson et al., 2005). We aimed at studying the function of viperin in human AoSMCs.Methods: Immunostaining of human carotid plaques was performed to determine the expression and localization of viperin in carotid plaques. To study the role of viperin in regulation of vascular inflammation, viperin was silenced using siRNA in cultured human AoSMCs, prior to stimulation with IFN-γ. Release of inflammatory mediators was analyzed using OLINK proteomics and ELISA, and the gene expression was analyzed by qRT-PCR.Results: Viperin is expressed in endothelial cells, macrophages and smooth muscle cells in human carotid plaques. OLINK data analysis revealed reduction in release of CCL3, CXCL9, CXCL10 and CXCL11 by AoSMCs that were targeted with anti-viperin siRNA prior to stimulation with IFN-γ. Using ELISA and qRT-PCR, we could confirm the reduction of IFN-γ-induced CXCL10 and CXCL11 in viperin knockdown AoSMCs.Conclusions: Viperin is expressed in human carotid plaques and seem to be involved in regulating the expression of CXCL10 and CXCL11 in AoSMCs. Thus, it may play a role in recruitment of T lymphocytes to the subendothelial space in atherosclerotic plaques.
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| 15. |
- Hayderi, Assim, 1990-, et al.
(författare)
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RSAD2 is abundant in atherosclerotic plaques and promotes interferon-induced CXCR3-chemokines in human smooth muscle cells
- 2024
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- In atherosclerotic lesions, monocyte-derived macrophages are major source of interferon gamma (IFN-γ), a pleotropic cytokine known to regulate the expression of numerous genes, including the antiviral gene RSAD2. While RSAD2 was reported to be expressed in endothelial cells of human carotid lesions, its significance for the development of atherosclerosis remains utterly unknown. Here, we harnessed publicly available human carotid atherosclerotic data to explore RSAD2 in lesions and employed siRNA-mediated gene-knockdown to investigate its function in IFN-γ-stimulated human aortic smooth muscle cells (hAoSMCs). Silencing RSAD2 in IFN-γ-stimulated hAoSMCs resulted in reduced expression and secretion of key CXCR3-chemokines, CXCL9, CXCL10, and CXCL11. Conditioned medium from RSAD2-deficient hAoSMCs exhibited diminished monocyte attraction in vitro compared to conditioned medium from control cells. Furthermore, RSAD2 transcript was elevated in carotid lesions where it was expressed by several different cell types, including endothelial cells, macrophages and smooth muscle cells. Interestingly, RSAD2 displayed significant correlations with CXCL10 (r = 0.45, p = 0.010) and CXCL11 (r = 0.53, p = 0.002) in human carotid lesions. Combining our findings, we uncover a novel role for RSAD2 in hAoSMCs, which could potentially contribute to monocyte recruitment in the context of atherosclerosis.
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| 16. |
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| 17. |
- Holster, Savanne, et al.
(författare)
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Faecal microbiota transfer in patients with microscopic colitis : a pilot study in collagenous colitis
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:12, s. 1454-1466
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Faecal microbiota transfer (FMT) consists of the infusion of donor faecal material into the intestine of patients with the aim to restore a disturbed gut microbiota. Methods: In this pilot study (NCT03275467), the effect of three repeated FMTs (day 0, two weeks, four weeks) was studied and followed up for six months in nine collagenous colitis (CC) patients, using two stool donors. Results: Five patients had an active disease at the time of baseline sampling. The primary endpoint (remission at six weeks, defined as <3 stools whereof <1 watery stool per day) was achieved by two of these patients, and by one at eight weeks. Overall, in all nine patients, FMT did not result in a significant reduction of watery stools, assessed by daily diary. However, diarrhoea (assessed by gastrointestinal symptom rating scale) was significantly improved at four (p = .038) and eight weeks (p = .038), indigestion at eight (p = .045) and 12 weeks (p = .006), disease-related worries at four (p = .027) and eight weeks (p = .027), and quality of life at six months (p = .009). FMT resulted in an increased number of lamina propria lymphocytes, possibly indicating an initial mucosal immune activation. No serious adverse events, no systemic effects, and no changes in faecal calprotectin and psychological symptoms were observed. Conclusions: FMT is able to improve symptoms in a yet undefined subset of CC patients. Further studies could help to characterise this subset and to understand if these results can be generalised to all microscopic colitis patients.
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| 18. |
- Kapetanaki, Stefania, 1988-, et al.
(författare)
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The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:21
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Tidskriftsartikel (refereegranskat)abstract
- Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, has previously been shown to be implicated in chronic kidney disease. A high TMAO-containing diet has been found to cause tubulointerstitial renal fibrosis in mice. However, today there are no data linking specific molecular pathways with the effect of TMAO on human renal fibrosis. The aim of this study was to investigate the fibrotic effects of TMAO on renal fibroblasts and to elucidate the molecular pathways involved. We found that TMAO promoted renal fibroblast activation and fibroblast proliferation via the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 signaling. We also found that TMAO increased the total collagen production from renal fibroblasts via the PERK/Akt/mTOR pathway. However, TMAO did not induce fibronectin or TGF-β1 release from renal fibroblasts. We have unraveled that the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 mediates TMAO's fibrotic effect on human renal fibroblasts. Our results can pave the way for future research to further clarify the molecular mechanism behind TMAO's effects and to identify novel therapeutic targets in the context of chronic kidney disease.
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| 19. |
- Kapetanaki, Stefania, 1988-, et al.
(författare)
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TMAO enhances TNF-α mediated fibrosis and release of inflammatory mediators from renal fibroblasts
- 2024
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite and TNF-α is proinflammatory cytokine, both known to be associated with renal inflammation, fibrosis and chronic kidney disease. However, today there are no data showing the combined effect of TMAO and TNF-α on renal fibrosis-and inflammation. The aim of this study was to investigate whether TMAO can enhance the inflammatory and fibrotic effects of TNF-α on renal fibroblasts. We found that the combination of TNF-α and TMAO synergistically increased fibronectin release and total collagen production from renal fibroblasts. The combination of TMAO and TNF-α also promoted increased cell proliferation. Both renal proliferation and collagen production were mediated through Akt/mTOR/ERK signaling. We also found that TMAO enhanced TNF-α mediated renal inflammation by inducing the release of several cytokines (IL-6, LAP TGF-beta-1), chemokines (CXCL-6, MCP-3), inflammatory-and growth mediators (VEGFA, CD40, HGF) from renal fibroblasts. In conclusion, we showed that TMAO can enhance TNF-α mediated renal fibrosis and release of inflammatory mediators from renal fibroblasts in vitro. Our results can promote further research evaluating the combined effect of TMAO and inflammatory mediators on the development of kidney disease.
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| 20. |
- Kapetanaki, Stefania, 1988-, et al.
(författare)
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TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:16
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Tidskriftsartikel (refereegranskat)abstract
- Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counteracted the suppressive effect of TMAO on megalin expression. Our results may further help us unravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.
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