| 1. |
- Engelbertsen, Daniel, et al.
(author)
-
IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis
- 2018
-
In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 114:1, s. 180-187
-
Journal article (peer-reviewed)abstract
- The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. Methods and results We transferred apoe-/-myd88\+/\+ or apoe-/-myd88-/- CD4+ T cells to T-A nd B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88\+/\+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-c. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. Conclusion We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.
|
|
| 2. |
- Engelbertsen, Daniel, et al.
(author)
-
Low Levels of IgM Antibodies against an Advanced Glycation Endproduct-Modified Apolipoprotein B100 Peptide Predict Cardiovascular Events in Nondiabetic Subjects.
- 2015
-
In: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 195:7, s. 3020-3025
-
Journal article (peer-reviewed)abstract
- Increased glucose levels are associated with the generation of advanced glycation endproduct (AGE) modifications. Interaction between AGE-modified plaque components and immune cells is believed to have an important role in the development of vascular complications in diabetes. Methylglyoxal (MGO) is one type of reactive aldehyde that gives rise to AGE modification. The present study analyzed whether autoantibodies against MGO-modified epitopes of the low-density lipoprotein apolipoprotein B (apoB) 100 predict cardiovascular events. A library consisting of 302 peptides comprising the complete apoB100 molecule was screened to identify peptides targeted by MGO-specific autoantibodies. Peptide (p) 220 (apoB amino acids 3286-3305) was identified as a major target. Baseline IgM and IgG against MGO-peptide 220 (p220) were measured in 700 individuals from the Malmö Diet and Cancer Cohort. A total of 139 cardiovascular events were registered during the 15-y follow-up period. Controlling for major cardiovascular risk factors demonstrated that subjects in the lowest tertile of MGO-p220 IgM had an increased risk for cardiovascular events (hazard ratio [95% confidence interval]: 2.07 [1.22-3.50]; ptrend = 0.004). Interestingly, the association between MGO-p220 IgM and cardiovascular events remained and even tended to become stronger when subjects with prevalent diabetes were excluded from the analysis (2.51 [1.37-4.61]; ptrend = 0.002). MGO-p220 IgM was inversely associated with blood glucose, but not with oxidized low-density lipoprotein. Finally, we demonstrate that anti-MGO-p220 IgM is produced by B1 cells. These data show that subjects with low levels of IgM recognizing MGO-modified p220 in apoB have an increased risk to develop cardiovascular events and that this association is present in nondiabetic subjects.
|
|
| 3. |
- Hsiung, Sabrina, et al.
(author)
-
Hyperglycemia does not affect tissue repair responses in shear stress-induced atherosclerotic plaques in ApoE-/-mice
- 2018
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Journal article (peer-reviewed)abstract
- The mechanisms responsible for macrovascular complications in diabetes remain to be fully understood. Recent studies have identified impaired vascular repair as a possible cause of plaque vulnerability in diabetes. This notion is supported by observations of a reduced content of fibrous proteins and smooth muscle cell mitogens in carotid endarterectomy from diabetic patients along with findings of decreased circulating levels of endothelial progenitor cells. In the present study we used a diabetic mouse model to characterize how hyperglycemia affects arterial repair responses. We induced atherosclerotic plaque formation in ApoE-deficient (ApoE-/-) and heterozygous glucokinase knockout ApoE-deficient mice (ApoE-/-GK+/-) mice with a shear stress-modifying cast. There were no differences in cholesterol or triglyceride levels between the ApoE-/-A nd ApoE-/-GK+/-mice. Hyperglycemia did not affect the size of the formed atherosclerotic plaques, and no effects were seen on activation of cell proliferation, smooth muscle cell content or on the expression and localization of collagen, elastin and several other extracellular matrix proteins. The present study demonstrates that hyperglycemia per se has no significant effects on tissue repair processes in injured mouse carotid arteries, suggesting that other mechanisms are involved in diabetic plaque vulnerability.
|
|
| 4. |
- Mantani, Polyxeni T., et al.
(author)
-
Interleukin-25 reduces Th17 cells and inflammatory responses in human peripheral blood mononuclear cells
- 2018
-
In: Human Immunology. - : Elsevier BV. - 0198-8859. ; 79:9, s. 685-692
-
Journal article (peer-reviewed)abstract
- Background: The absence of interleukin-25 (IL-25) favors the induction of Th1 and Th17 immune responses in mice. Th1 immune responses have been associated with the pathology of atherosclerosis, a lipid and inflammation driven disease of the arterial wall. Purpose of research: To evaluate the effect of IL-25 on human peripheral blood mononuclear cells (hPBMCs) in the presence and absence of oxidized low density lipoprotein (oxLDL), a key player in atherosclerosis development. Principal results: Human PBMCs were incubated with recombinant human IL-25 (rhIL-25) in the presence and absence of oxLDL and analyzed with flow cytometry while cytokine secretion was measured in cell culture supernatants. The IL-25 receptor, IL-17RB, was mostly expressed on T cells. Incubation of hPBMCs with IL-25 reduced the frequency of Th17 cells. Furthermore, IL-25 inhibited the release of the Th17-inducing cytokine IL-6 from dendritic cells isolated from hPBMCs indicating that the IL-25 mediated Th17 suppression may be indirect. Moreover, IL-25 reduced the secretion of the proinflammatory cytokine IFNγ from hPBMCs. OxLDL decreased IFNγ release from hPBMCs regardless of the presence or absence of IL-25. Conclusions: IL-25 reduces Th1 and Th17 immune responses in hPBMCs raising the interesting possibility that IL-25 could have a protective role in human atherosclerosis.
|
|
| 5. |
|
|
