Immune response – NF-kB activation
Innate and adaptive immunity are involved in chronic hypertension and
vascular damage. The Ang II/aldosterone/peroxynitrite axis activates the
key inflammatory gene transcriptor NF-kB to evoke genomic production of
inflammatory cytokines such as Il-1, Il-6 and TNF-a, adhesion molecules
(ICAM-1), chemokines, coagulation factors such as von Willebrand’s
Factor and IL-18 and plasminogen activator (t-PA) which promote clotting
and collagens to promote fibrosis. Aldosterone and Ang II produce a
concerted and interactive oxidative and inflammatory cascade by
activating most of the cell types found in and around the cardiovascular
system, including cardiomyocytes, vascular smooth muscle cells,
mesangial cells and podocytes, fibroblasts and immune cells. Aldosterone
induces macrophage and T-lymphocyte vascular infiltration through MRs
expressed in both of these cell types. Aldosterone produces an M1
proinflammatory phenotype in macrophages through ROS-mediated activation
of the NLRP3 inflammasome and can result in Macrophage Activation
Syndrome. MR-activated T-lymphocytes infiltrate the cardiovascular
system and secrete inflammatory mediators such as interferon-gamma
(IFN-y), interleukins and TNF-a. There is a profound increase in
CD8+ IFN-y T cells, while regulatory T lymphocytes
(Tregs), suppressors of the innate and adaptive immune response, are
reduced, priming the system for an acute inflammatory response that is
directly associated with COVID-19 severity. (9)