Regulation of immune cells in atherosclerosis and its clinical implications: The role of A-to-I editing and interleukin 6 receptor inhibition

Recruitment of immune cells to the developing atherosclerotic plaques is a hallmark in the atherosclerotic process. Immune cell recruitment is also a major factor following acute cardiovascular events in atherosclerosis, such as myocardial infarction and stroke, where there is massive recruitment to the site of injury. To identify treatment targets, there is a need to better understand the immunopathogenic mechanism in the atherosclerotic process and its related clinical implications. In this thesis, we aimed to: (i) assess the impact of Endonuclease V (EndoV), an enzyme known to cleave adenosine-to-inosine (A-to-I) modified RNA, on the immune cell response in atherogenesis and stroke, and (ii) investigate the effect of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, on the immune cell levels and responses in patients during ST-elevation myocardial infarction (STEMI). In human carotid atherosclerotic plaques, we found higher levels of EndoV and A-to-I editing than in non-atherosclerotic arteries. Absence of EndoV gave a reduced atherosclerotic plaque burden, both in lipid content and lesion size, with reduced monocyte recruitment in mice. In addition, abolishment of EndoV seemed to have protective effects on brain damage in a murine hypoxia-ischemic stroke model. Inhibition of the IL-6 signaling pathway in STEMI patients is beneficial for the patient outcome. This thesis shows that tocilizumab reduced neutrophil and monocyte counts without affecting lymphocyte counts in the circulation following STEMI. Tocilizumab dampened the inflammatory responses in neutrophils with neutrophil degranulation, while monocytes had an upregulation of several cytokine signaling pathways with potential beneficial effects on myocardial remodeling and inflammation. These changes might contribute to the observed improved outcome for the tocilizumab treated patients