liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Pro- and anti-inflammatory actions in coronary artery disease: with focus on CD56+ T cells and Annexin A1
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

¨The atherosclerotic process is considered to be driven by an imbalance between proand anti-inflammatory actions. Still, the inflammatory state in patients with coronary artery disease (CAD) remains to be clarified. Annexin A1 (AnxA1) is a glucocorticoidinduced protein which may have a key role in the anti-inflammatory response as a mediator of glucocorticoid effects.

The general aim of this thesis was to deepen the knowledge of pro- and antiinflammatory mechanisms in CAD via phenotypic assessments of immune cell subsets, in particular CD56+ T cells, and exploration of AnxA1. The long-term goal is to reveal basic mechanisms that will lead to the development of biomarkers, which may be used for individualized treatment and monitoring.

The AnxA1 protein was constitutively expressed in both neutrophils and peripheral blood mononuclear cells (PBMCs). However, it varied considerably across PBMC subsets, being most abundantly expressed in monocytes. The AnxA1 expression was also higher in CD56+ T cells than in CD56- T cells.

The expression of total AnxA1 protein in neutrophils was higher in patients with stable angina (SA) compared with controls. However, this was not accompanied by altered neutrophil activation status. Instead, the neutrophils from patients exhibited an enhanced anti-inflammatory response to exogenous AnxA1, emphasizing the potential of AnxA1 as an inhibitor of neutrophil activity. Only patients with acute coronary syndrome (ACS) showed an increase in cell surface-associated AnxA1.

CAD patients, independent of clinical presentation, had increased proportions of CD56+ T cells compared with controls, a phenomenon likely to represent immunological aging. The CD56+ T cells were found to exhibit a distinct proinflammatory phenotype compared with CD56- T cells. In all T cell subsets, the expression of cell surface-associated AnxA1 was significantly increased in ACS patients, while it tended to be increased in post-ACS patients. In addition, dexamethasone clearly inhibited activation of CD56+ T cells in in vitro assays, whereas AnxA1 did not. The findings highlight the need to clarify whether the role of AnxA1 is different in T cells than in innate immune cells.

In PBMCs, the mRNA levels of AnxA1 were increased in CAD patients, particularly in ACS patients. Correspondingly, the monocytes in ACS patients exhibited increased AnxA1 protein levels, both totally and on the cell surface. However, only cell surface-associated AnxA1 in monocytes correlated with the glucocorticoid sensitivity of PBMCs ex vivo. We propose the expression of cell surfaceassociated AnxA1 to be a promising candidate marker of glucocorticoid sensitivity, which needs further investigations in larger cohorts and intervention trials. Furthermore, the fact that PBMCs in post-ACS patients exhibited pro-inflammatory activity but no increase in cell surface-associated AnxA1 allow us to speculate that the glucocorticoid action and/or availability might be insufficient in these patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1437
National Category
Cardiac and Cardiovascular Systems Immunology in the medical area Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-114123DOI: 10.3384/diss.diva-114123ISBN: 978-91-7519-150-8 (print)OAI: oai:DiVA.org:liu-114123DiVA: diva2:787338
Public defence
2015-03-13, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2015-02-10Bibliographically approved
List of papers
1. Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
Open this publication in new window or tab >>Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
Show others...
2010 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 59, no 3, 443-440 p.Article in journal (Refereed) Published
Abstract [en]

Background: A dysregulated cortisol response in patients with stable coronary artery disease (CAD) is related to systemic inflammatory activity. Moreover, a dysfunctional activation status of neutrophils in CAD has been discussed. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1), a protein mainly expressed by innate immune cells. An altered expression of glucocorticoid receptors (GR) and ANXA1 has been associated with glucocorticoid resistance.

Methods and Results: Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in neutrophil stimulation assays. The patients showed a flattened diurnal cortisol pattern compared to healthy subjects, involving higher levels in the evening. The neutrophil expression of GRtotal and GRα, as well as the ratio of GRα:GRβ expression was significantly decreased in patients, whereas the GRβ expression did not differ compared to controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 suppressed LTB4-induced ROS production in neutrophils from patients, but not from controls. On the other hand, ANXA1 impaired the LTB4-induced up-regulation of β2-integrins in both patients and controls.

Conclusion: CAD patients displayed a more flattened diurnal cortisol rhythm caused by higher cortisol levels in the evening compared to healthy subjects. Our findings indicate a chronic overactivation of the hypothalamic-pituitary-adrenal (HPA) axis but give no conclusive evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The data rather point towards an increased anti-inflammatory potential in neutrophils from patients with stable CAD.

Keyword
Coronary artery disease, cortisol, neutrophil, glucocorticoid receptor, annexin-1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17247 (URN)10.1016/j.metabol.2009.07.044 (DOI)000276761800021 ()
Note
Original Publication: Eva Särndahl, Ida Bergström, Johnny Nijm, Tony Forslund, Mauro Perretti and Lena Jonasson, Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease, 2010, Metabolism: Clinical and Experimental, (59), 3, 443-440. http://dx.doi.org/10.1016/j.metabol.2009.07.044 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2017-12-13
2. Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease
Open this publication in new window or tab >>Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease
Show others...
2012 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 2, 515-520 p.Article in journal (Refereed) Published
Abstract [en]

Objective: There is emerging evidence for CD8(+) T cell alterations in blood from patients with coronary artery disease (CAD). We examined whether the distribution and phenotype of CD8(+)CD56(+) T cells differed according to the clinical manifestation of CAD. less thanbrgreater than less thanbrgreater thanMethods: Patients with acute coronary syndrome (ACS, n = 30), stable angina (SA, n = 34) and controls (n = 36) were included. Blood was collected before and up to 12 months after referral for coronary investigation. CD8(+)CD56(+) T cells were assessed by flow cytometry for expression of surface markers, apoptosis, and intracellular expression of cytokines. less thanbrgreater than less thanbrgreater thanResults: The proportions of CD8(+)CD56(+) T cells were significantly higher in both ACS and SA patients compared with controls, and remained so after 3 and 12 months. This was independent of age, sex, systemic inflammation and cytomegalovirus seropositivity. CD8(+)CD56(+) T cells differed from CD8(+)CD56(-) T cells in terms of lower CD28 expression and fewer apoptotic cells. Both CD8(+) T cell subsets were positive for interferon (IFN)-gamma and tumor necrosis factor, although IFN-gamma was significantly more confined to the CD8(+)CD56(+) T cells. less thanbrgreater than less thanbrgreater thanConclusion: The persistent accumulation of CD8(+)CD56(+) T cells in ACS and SA patients share several features with immunological aging. It also contributes to a larger IFN-gamma(+) pool in blood, and may thereby hypothetically drive the atherosclerotic process in a less favorable direction.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Acute coronary syndrome, Coronary artery disease, Cytokines, Immune system, Leukocytes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84895 (URN)10.1016/j.atherosclerosis.2012.07.033 (DOI)000309261400039 ()
Note

Funding Agencies|Swedish Research Council||Swedish Heart-Lung Foundation||County Council of Ostergotland, Sweden||Eleanora Demeroutis Foundation, Linkoping, Sweden||Heart Foundation at Linkoping University, Linkoping, Sweden||

Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2017-12-07
3. Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells: Potential implications for coronary artery disease
Open this publication in new window or tab >>Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells: Potential implications for coronary artery disease
Show others...
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Increased proportions of circulating proinflammatory CD56+ T cells have been reported in patients with coronary artery disease (CAD). Yet, little is known about regulation of these cells. In the present study, we investigated the expression and potential role of the glucocorticoid-mediated protein annexin A1 (AnxA1) in CD56+ and CD56-T cell subsets, with focus on CAD.

Methods and Results: We included totally 52 healthy individuals, 28 patients with acute coronary syndrome (ACS) and 57 patients with a history of ACS. AnxA1 mRNA expression was assessed in peripheral blood mononuclear cells. AnxA1 protein expression (total and cell surface-associated) was measured by whole blood flow cytometry in circulating CD56+ and CD56- T cell subsets. Furthermore, inhibitory effects of dexamethasone and/or recombinant AnxA1 on cytokine secretion by CD56+ and CD56- T cells were explored in vitro. We found that CD56+ T cells (the majority CD8+), expressed higher levels of AnxA1 mRNA and protein than did CD56- T cells. When comparing CAD patients with healthy controls, significantly higher levels of cell surface-associated AnxA1 expression were seen in patients, most pronounced in ACS patients. In vitro, dexamethasone reduced cytokine secretion by CD56+ T cells, whereas AnxA1 alone had no effect, and AnxA1 combined with dexamethasone abolished the dexamethasone-induced suppressive effects.

Conclusion: AnxA1 was expressed more abundantly in proinflammatory CD56+ T cells. Patients with ACS exhibited increased levels of cell surface-associated AnxA1, thus indicating increased activation of the AnxA1 pathway. Our data further suggested that AnxA1 might counteract glucocorticoid mediated anti-inflammatory effects in T cells.

Keyword
Annexin A1, T cell, CD56, coronary artery disease, acute coronary syndrome
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114121 (URN)
Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2015-03-30Bibliographically approved
4. Annexin A1 expression in blood mononuclear cells: a potential marker of glucocorticoid activity in patients with coronary artery disease
Open this publication in new window or tab >>Annexin A1 expression in blood mononuclear cells: a potential marker of glucocorticoid activity in patients with coronary artery disease
Show others...
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

An imbalance between pro- and anti-inflammatory actions is believed to drive progression of atherosclerosis. Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of anti-inflammatory effects of glucocorticoids. Here, we investigated whether expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) was altered in patients with coronary artery disease (CAD) and also related findings to glucocorticoid sensitivity ex vivo.

We included 57 patients 6-12 months after acute coronary syndrome (ACS), 10 patients with ACS, and healthy controls. AnxA1 mRNA was measured in PBMCs and AnxA1 protein was assessed in monocytes and lymphocyte subsets by flow cytometry. In post-ACS patients and controls, glucocorticoid sensitivity was determined by measuring inhibitory effects of dexamethasone on LPS46 induced cytokine secretion.

AnxA1 mRNA levels in PBMCs were higher in patients compared with controls, although most pronounced in ACS patients. AnxA1 protein was most abundant in the monocyte fraction. ACS patients exhibited the highest levels of cell surface-associated AnxA1 protein while levels in post-ACS patients and controls were similar. Ex vivo assays showed that PBMCs from post-ACS patients were more prone to release IL-6. Glucocorticoid sensitivity correlated with cell surface-associated AnxA1 protein in peripheral monocytes. Dexamethasone also induced upregulation of AnxA1 mRNA.

AnxA1 expression in PBMCs is closely associated with glucocorticoid actions and cell surface associated AnxA1 appears to be a marker of glucocorticoid sensitivity. Although still speculative, a “normal” expression of cell surface-associated AnxA1 in post-ACS patients may suggest that glucocorticoid actions in vivo are insufficient to provide adequate anti-inflammatory effects in these patients.

Keyword
Annexin A1, monocytes, glucocorticoids, coronary artery disease, acute coronary syndrome
National Category
Cardiac and Cardiovascular Systems Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114122 (URN)
Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2015-03-30Bibliographically approved

Open Access in DiVA

fulltext(2140 kB)361 downloads
File information
File name FULLTEXT01.pdfFile size 2140 kBChecksum SHA-512
5df185f853afa23c18da023930ad76f37913a7784f700b3211e1d1c756bbd81579cf85639e8c50ea4acf8de8ed3c2a5b8f223fb756409a040bca2df016fc8c7a
Type fulltextMimetype application/pdf
omslag(3409 kB)29 downloads
File information
File name COVER01.pdfFile size 3409 kBChecksum SHA-512
1a20aab7743a7da14791aec3ca33062d67fa34fee8a5e6216af750d6897b24fd0de2e47e8cd136955a4905978a8e0f7e97db3a924eb799ac9ec3f1e3bc819d35
Type coverMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Bergström, Ida

Search in DiVA

By author/editor
Bergström, Ida
By organisation
Division of Cardiovascular MedicineFaculty of Health Sciences
Cardiac and Cardiovascular SystemsImmunology in the medical areaMedical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 361 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 986 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf