Inflammation by activation of the RAS axis
The central role of the RAS pathway in inflammation came to light after the SARS pandemic in 2002. An elevated ACE/ACE2 activity ratio after the downregulation of ACE2 increases the available angiotensin II. AT1 receptor pathway dominates over the AT2 pathway due to its wider distribution and higher expression.17 Activation of AT1 produces different effects in the tissue-localized RAS and the RAS localized to the immune system.
The tissue effect of RAS dysregulation is multipronged in the pathogenesis of COVID-19. Activation of the AT1 receptor mediates inflammation by transcription of NF-κB and the production of pro-inflammatory cytokines like IL-6.18 The interaction between the S-protein of the virus and the ACE2 receptor increases CCL2 production by a separate ERK1/2 pathway.19 In mice, ACE inhibition reduced CCL2 levels and the recruitment of inflammatory cells.20 The latter two imply an increase in chemokine production leading to the homing of macrophages and dendritic cells. Evidence that tissue inflammation occurs due to the recruitment of inflammatory cells rather than direct T-cell activation comes from mouse models. Studies have shown that AT1 mediated tissue injury occurs despite the transplant of AT1 devoid bone marrow.21,22 Angiotensin II can lead to early neutrophil accumulation through IL-8 production as studied in human umbilical vein endothelial cells.23 ACE activity also enhances neutrophil activation and reactive oxygen species production.24 These pathways stimulate tissue-specific inflammation leading to ARDS or acute cardiac injury.
The effect of AT1 activation on the immune system is different; it inactivates the immune system. AT1 knockout T-cells in mice showed increased T-bet expression, producing more IFN-γ and TNF-α.25 AT1 knockout macrophages in mice also produced more TNF and IL-1β.26 The stimulation of AT1 on T-cells and macrophages curbed their polarization.
The above research suggests that RAS activation in COVID-19 damages tissue by recruiting inflammatory cells rather than direct activation of the immune system. This might throw light on single organ dysfunction (like ARDS) in patients with well-preserved function of other organ systems. Tempering and negative regulation of T-cells, and increased neutrophil recruitment explains the poor prognosis in patients with increased neutrophil to lymphocyte ratio.