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.