Neuroinflammation and COVID-19 Ischemic Stroke Recovery-Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis and NLRP3 Inflammasome

Abstract

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1-7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.

Keywords: ACE2; COVID-19; NLRP3 inflammasome; ischemic stroke; neurorehabilitation.

Figure 1

Pathophysiological mechanism of COVID-19-mediated ischemic stroke and its common or shared features with that of AIS. ACE2, angiotensin-converting enzyme 2; CHD, coronary heart disease; ECs, endothelial cells; HPT, hypertension; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus; TF, tissue factors; vWF, von Willebrand factor.

Figure 2

Possible mechanism of COVID-19-mediated ischemic stroke due to SARS-CoV-2-infection-mediated downregulation of angiotensin-converting enzyme 2 (ACE2) from renin angiotensin system (RAS). Reduced expression of ACE2 inhibits the conversion of angiotensin II to Ang-(1-7) and of angiotensin 1 to Ang-(1-9). Reduced Ang-(1-7) activity and its axis with mitochondrial assembly receptor (MasR) interfere with the anti-inflammatory, anti-apoptosis, anti-fibrosis, and vasodilation effect, thereby increasing blood–brain barrier (BBB) permeability and damage. Furthermore, the overactivation of angiotensin II binds to its angiotensin II type 1 receptor (AT1R), promoting further inflammation, vasoconstriction, fibrosis, and proliferation, thereby increasing secondary (2°) neuro-glial cell injury, leading to neuroinflammation and, finally, brain ischemia. CHD, coronary heart disease; HPT, hypertension; T2DM, type 2 diabetes mellitus.

Figure 3

Brief mechanism of NLRP3 inflammasome activation and its role in acute ischemic stroke (AIS) and COVID-19-mediated ischemic stroke. Upon viral infection and subsequent increases in thrombo-inflammation and blood–brain barrier (BBB) breakdown, the heightened oxidative stress promotes higher activity of adenosine triphosphate (ATP), activating purinergic ligand-gated ion channel 7 receptor (P2X7R), thereby increasing calcium ion (Ca²⁺) inflow and potassium ion (K⁺) outflow. These, in turn, increase reactive oxygen species (ROS) production. A higher production of ROS can also be induced by oxidative-stress-mediated mitochondrial dysfunction and the inhibition of the thioredoxin (TRX) system by TRX-interacting protein (TRXNIP). The increased ROS then activates the NLRP3 inflammasome. Furthermore, increased ROS-mediated NLRP3 inflammasome can also be mediated by ischemic mediated endoplasmic reticulum (ER) stress, which increases intracellular Ca²⁺ lysosomal membrane rupture, which in turn activates NLRP3 receptor incision through cathepsin and activated protein kinase R (PKR) by double-stranded RNA. The activated NLRP3 inflammasome promotes the pro-caspase self-cleavage into caspase-1; next, the caspase-1 lyses and activates gasdermin-D-mediated cell death (GSDMD) and pro-inflammatory cytokines (i.e., interleukin-18 and -1β), leading to neuro-glial cell death or pyroptosis, inducing or worsening AIS or COVID-19-mediated ischemic stroke. ASC, apoptosis-associated speck-like protein containing a CARD subunit.

Figure 4

Proposed mediating role of ACE2/Ang-(1-7)/MasR axis and NLRP3 inflammasome in AIS and COVID-19-mediated ischemic stroke and the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.