| 1. |
- Levin, Malin, 1973, et al.
(författare)
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Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation.
- 2011
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Ingår i: Circulation research. - 1524-4571. ; 109:11, s. 1210-8
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Tidskriftsartikel (refereegranskat)abstract
- The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-κB (NFκB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.
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| 2. |
- Pelaseyed, Thaher, 1979, et al.
(författare)
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The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system
- 2014
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Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 260:1, s. 8-20
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Forskningsöversikt (refereegranskat)abstract
- The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
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| 3. |
- Bergström, Joakim H., 1977, et al.
(författare)
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AGR2, an endoplasmic reticulum protein, is secreted into the gastrointestinal mucus.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- The MUC2 mucin is the major constituent of the two mucus layers in colon. Mice lacking the disulfide isomerase-like protein Agr2 have been shown to be more susceptible to colon inflammation. The Agr2(-/-) mice have less filled goblet cells and were now shown to have a poorly developed inner colon mucus layer. We could not show AGR2 covalently bound to recombinant MUC2 N- and C-termini as have previously been suggested. We found relatively high concentrations of Agr2 in secreted mucus throughout the murine gastrointestinal tract, suggesting that Agr2 may play extracellular roles. In tissue culture (CHO-K1) cells, AGR2 is normally not secreted. Replacement of the single Cys in AGR2 with Ser (C81S) allowed secretion, suggesting that modification of this Cys might provide a mechanism for circumventing the KTEL endoplasmic reticulum retention signal. In conclusion, these results suggest that AGR2 has both intracellular and extracellular effects in the intestine.
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| 4. |
- Bernberg, Evelina, 1981, et al.
(författare)
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Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE-/- mice.
- 2012
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 221:2, s. 359-65
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that different forms of stress have distinctive effects on atherogenesis in mice. We showed that social stress increase atherosclerosis in ApoE(-/-) mice, while more physical forms of stress do not. Here we evaluated the effect of social disruption (SDR) stress on atherogenesis and evaluated cytokine release after SDR-stress and five more physical stressors.
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| 5. |
- Bu, D. X., et al.
(författare)
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Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair
- 2010
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Ingår i: Arterioscler Thromb Vasc Biol. - 1524-4636 .- 1079-5642. ; 30:12, s. 2604-10
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process by investigating expression and function of the catalytic telomerase reverse transcriptase (TERT) subunit after vascular injury. METHODS AND RESULTS: Functional telomerase is essential to the replicative longevity of vascular cells. We found that TERT was de novo activated in the intima of injured arteries, involving activation of the nuclear factor kappaB pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor alpha resulted in increased TERT activity. This depends on the activation of c-Myc signaling because mutation of the E-box in the promoter or overexpression of mitotic arrest deficient 1 (MAD1), a c-Myc competitor, abrogated the transcriptional activity. Inhibition of nuclear factor kappaB in both intimal SMCs and the injured artery attenuated TERT transcriptional activity through reduction of c-Myc expression. Pharmacological blockade of TERT led to SMC senescence. Finally, depletion of telomerase function in mice resulted in severe intimal SMC senescence after vascular injury. CONCLUSIONS: These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor kappaB and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.
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| 6. |
- Darsalia, V., et al.
(författare)
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Exendin-4 Reduces Ischemic Brain Injury in Normal and Aged Type 2 Diabetic Mice and Promotes Microglial M2 Polarization
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Exendin-4 is a glucagon-like receptor 1 agonist clinically used against type 2 diabetes that has also shown neuroprotective effects in experimental stroke models. However, while the neuroprotective efficacy of Exendin-4 has been thoroughly investigated if the pharmacological treatment starts before stroke, the therapeutic potential of the Exendin-4 if the treatment starts acutely after stroke has not been clearly determined. Further, a comparison of the neuroprotective efficacy in normal and aged diabetic mice has not been performed. Finally, the cellular mechanisms behind the efficacy of Exendin-4 have been only partially studied. The main objective of this study was to determine the neuroprotective efficacy of Exendin4 in normal and aged type 2 diabetic mice if the treatment started after stroke in a clinically relevant setting. Furthermore we characterized the Exendin-4 effects on stroke-induced neuroinflammation. Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion. 5 or 50 mg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter. The treatment was continued (0.2 mg/kg/day) for 1 week. The neuroprotective efficacy was assessed by stroke volume measurement and stereological counting of NeuN-positive neurons. Neuroinflammation was determined by gene expression analysis of M1/M2 microglia subtypes and proinflammatory cytokines. We show neuroprotective efficacy of 50 mg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice. The 5 mu g/kg dose was neuroprotective at 1.5 hour only. Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated. Our results support the use of Exendin-4 to reduce stroke-damage in the prehospital/early hospitalization setting irrespectively of age/diabetes. The results indicate the polarization of microglia/macrophages towards the M2 reparative phenotype as a potential mechanism of neuroprotection.
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| 7. |
- Hua, Sansan, et al.
(författare)
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Perinatal Hypoxia-Ischemia Reduces alpha 7 Nicotinic Receptor Expression and Selective alpha 7 Nicotinic Receptor Stimulation Suppresses Inflammation and Promotes Microglial Mox Phenotype
- 2014
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Ingår i: Biomed Research International. - : Hindawi Limited. - 2314-6133 .- 2314-6141.
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, alpha 7 nicotinic acetylcholine receptors (alpha 7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated alpha 7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti-inflammatory role of alpha 7R stimulation in vitro and microglia polarization after alpha 7R agonist treatment. Real-time PCR analysis showed a 33% reduction in alpha 7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective alpha 7R agonist AR-R 17779 significantly attenuated TNF alpha release and increased alpha 7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or alpha 7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after alpha 7R stimulation. Thus, our data suggest a role for the alpha 7R also in the neonatal brain and support the anti-inflammatory role of alpha 7R in microglia, suggesting that alpha 7R stimulation could enhance the polarization towards a reparative Mox phenotype.
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| 8. |
- Johansson, Maria E, 1977, et al.
(författare)
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alpha 7 Nicotinic Acetylcholine Receptor Is Expressed in Human Atherosclerosis and Inhibits Disease in Mice-Brief Report
- 2014
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 34:12, s. 2632-2636
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Cholinergic pathways of the autonomic nervous system are known to modulate inflammation. Because atherosclerosis is a chronic inflammatory condition, we tested whether cholinergic signaling operates in this disease. We have analyzed the expression of the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) in human atherosclerotic plaques and studied its effects on the development of atherosclerosis in the hypercholesterolemic Ldlr(-/-) mouse model. Approach and Results-alpha 7nAChR protein was detected on T cells and macrophages in surgical specimens of human atherosclerotic plaques. To study the role of alpha 7nAChR signaling in atherosclerosis, male Ldlr(-/-) mice were lethally irradiated and reconstituted with bone marrow from wild-type or alpha 7nAChR-deficient animals. Ablation of hematopoietic cell alpha 7nAChR increased aortic atherosclerosis by 72%. This was accompanied by increased aortic interferon-gamma mRNA, implying increased Th1 activity in the absence of a7nAChR signaling. Conclusions-The present study shows that signaling through hematopoietic alpha 7nAChR inhibits atherosclerosis and suggests that it operates by modulating immune inflammation. Given the observation that alpha 7nAChR is expressed by T cells and macrophages in human plaques, our findings support the notion that cholinergic regulation may act to inhibit disease development also in man.
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| 9. |
- Johansson, Maria E, 1977, et al.
(författare)
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Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice
- 2014
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 44:10, s. 3081-3092
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-kappa B-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.
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| 10. |
- Johansson, Malin E V, 1971, et al.
(författare)
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Composition and functional role of the mucus layers in the intestine.
- 2011
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Ingår i: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 68, s. 3635-3641
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Forskningsöversikt (refereegranskat)abstract
- In discussions on intestinal protection, the protective capacity of mucus has not been very much considered. The progress in the last years in understanding the molecular nature of mucins, the main building blocks of mucus, has, however, changed this. The intestinal enterocytes have their apical surfaces covered by transmembrane mucins and the whole intestinal surface is further covered by mucus, built around the gel-forming mucin MUC2. The mucus of the small intestine has only one layer, whereas the large intestine has a two-layered mucus where the inner, attached layer has a protective function for the intestine, as it is impermeable to the luminal bacteria.
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