Cellular immunity and inflammation in atherosclerosis

Atherosclerosis, the major cause of death and disability in western countries, is nowadays recognized as an inflammatory disease. Low density lipoprotein (LDL), the major carrier of cholesterol in plasma, is trapped in the subendothelial space, where compounds inside of LDL are chemically modified through lipid peroxidation. The oxidized LDL (oxLDL) is believed to initiate the inflammatory reaction in atherosclerosis. By activation of the endothelial cell layer, cells of the immune system (monocytes and T lymphocytes, T cells) are recruited to developing atherosclerotic lesions. Monocytes differentiated into macrophages, which engulf oxLDL through specialized scavenger receptors leading to accumulation of cholesterol in the vessel wall, so-called foam cell formation. Macrophages may also activate T cells, which in turn secrete cytokines. Previous data have shown that oxLDL can activate T cells, but the molecular mechanisms have not been identified.

Oxidation of fatty acids in LDL generates reactive aldehydes that modify proteins. Two important aldehydes are malondialdehyde (MDA) and 4-hydroxynonenal, which can form covalent adducts on proteins. To analyze the mechanisms for the activation of T cells by aldehyde-modified proteins, T cells that were activated by MDA- or HNE-modified self-proteins were established in a mouse model. MDA modified self- proteins triggered T cells that directly recognized the MDA adduct with their T cell receptors. This finding demonstrates that lipid peroxidation derived aldehydes may turn selfproteins into antigens that can initiate a T cell mediated inflammatory reaction. These T cells may also activate B cells to secrete antibodies that are directed either towards the modifications or towards unmodified sequences of altered proteins.

To study the inflammatory response during atherosclerotic plaque development gene expression array technology was applied in a mouse model of atherosclerosis. The expression of previously known atherosclerosis related genes, e.g. the expression of adhesion molecules and markers of blood derived inflammatory cells, were used to validate the experimental procedure. The gene array analysis revealed that the cytokine interleukin-15 (IL-15) was expressed in the vessel wall and upregulated in atherosclerotic plaques. IL-15 expression could be identified in macrophage rich areas of the lesions supporting the hypothesis that IL-15 may be involved in the recruitment of T cells to the atherosclerotic lesion.

The gene array analysis identified the expression of cellular retinoic acid binging protein-II, a gene that is regulated by vitamin A signaling pathways. This finding led us to study effects of vitamin A on foam cell formation. The vitamin A derivative all-trans retinoic acid was shown to upregulate the expression scavenger receptor CD36 through retinoic acid receptor (RAR) signaling path in the human monocytic cell line THP-1. The RAR signaling path was identified in human atherosclerotic lesion associated with infiltrating leukocytes. This suggests that RAR-signaling may contribute to the inflammation in the vessel wall and promote atherosclerosis.

List of scientific papers

I. Wuttge DM, Bruzelius M, Stemme S (1999). "T-cell recognition of lipid peroxidation products breaks tolerance to self proteins. " Immunology 98(2): 273-9
https://pubmed.ncbi.nlm.nih.gov/10540227

II. Wuttge DM, Bruzelius M, Lundahl A, Paulsson G, Bergman T, Stemme S (2001). "Malondialdehyde epitopes are recognized as haptens by T cells." (Manuscript)

III. Wuttge DM, Sirsjo A, Eriksson P, Stemme S (2001). "Gene expression in atherosclerotic lesion of ApoE deficient mice. " Mol Med 7(6): 383-92
https://pubmed.ncbi.nlm.nih.gov/11474131

IV. Wuttge DM, Eriksson P, Sirsjo A, Hansson GK, Stemme S (2001). "Expression of interleukin-15 in mouse and human atherosclerotic lesions. " Am J Pathol 159(2): 417-23
https://pubmed.ncbi.nlm.nih.gov/11485899

V. Wuttge DM, Romert A, Eriksson U, Torma H, Hansson GK, Sirsjo A (2001). "Induction of CD36 by all-trans retinoic acid: retinoic acid receptor signaling in the pathogenesis of atherosclerosis. " FASEB J 15(7): 1221-3
https://pubmed.ncbi.nlm.nih.gov/11344094