Inflammation, immunity, and hypertensive end-organ damage

Abstract

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

Keywords: angiotensin II; antigen presenting cell; cytokines; effector T cell; nitric oxide synthase; sodium.

Figure 1

Classical pathway for T cell activation. Antigen presenting cells, including dendritic cells, B cells, macrophages and others process foreign antigens to peptides and present these in major histocompatibility complexes (MHC). MHC-I present to CD8⁺ T cells, while MHC-II present to CD4⁺ T cells. The peptide/MHC complex is recognized by a unique T cell receptor (TCR), representing signal 1. In addition, other receptor/ligand interactions occur which together with the TCR/MHC interaction for the immunological synapse. One such signal is the co-stimulatory interaction between CD28 and the B7 ligands, referred to as Signal 2. In the absence of this interaction full T cell activation does not occur. T cells possess numerous accessory receptors that modify response to Signals 1 and 2, proliferation and cytokine production (Signal 3).

Figure 2

T cell activation by isoketal protein modification. Hypertension induces production of reactive oxygen species (ROS) in dendritic cells (DCs), leading to oxidation of arachidonic acid and formation of gamma ketoaldehydes or isoketals. Isoketals rapidly ligate to protein lysines in the DC, forming proteins that are recognized as non-self. Peptides from these are presented to T cells, leading to T cell proliferation. Isoketal formation also promotes DC production of cytokines including IL-1β, IL-6 and IL-23, which polarize T cells to produce specific cytokines.

Figure 3

Cytokines and end-organ dysfunction in hypertension. A) In vessels T cells infiltrate the adventitia and perivascular fat through the vasa vasorum. T cell-derived IL-17A acts on smooth muscle cells and adventitial fibroblasts to increase eNOS phosphorylation, reactive oxygen species (ROS) production, collagen synthesis, and chemokine production leading to a decrease in bioavailable nitric oxide (NO) and impaired vasodilation, increased vascular stiffness, and increased recruitment of immune cells, propagating the inflammatory response. These effects result in vascular dysfunction. B) In the renal medulla and cortex, activated T cells produce cytokines such as IL-6 and IFNγ that stimulate production of angiotensinogen. Angiotensinogen is converted to angiotensin I (Ang I) by intrarenal renin and subsequently to angiotensin II (Ang II) by intrarenal angiotensin converting enzyme. Angiotensin II upregulates and stimulates transport channels in the proximal and distal convoluted tubules including the sodium hydrogen exchanger 3 (NHE3) and sodium chloride co-transporter (NCC). In conjunction with salt and water retention, T cell activation causes an increase in renal ROS production, and renal injury and fibrosis, all of which lead to renal dysfunction. The culmination of vascular and renal dysfunction caused by T cell derived cytokines exacerbates hypertension. (Illustration credit: Ben Smith).