The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation

Abstract

Angiotensin converting enzyme 2 (ACE2) plays an important role in inflammation, which is attributable at least, in part, to the conversion of the pro-inflammatory angiotensin (Ang) II peptide into angiotensin 1-7 (Ang 1-7), a peptide which opposes the actions of AngII. ACE2 and AngII are present in many tissues but information on the cornea is lacking. We observed that mice deficient in the Ace2 gene (Ace2 −/−), developed a cloudy cornea phenotype as they aged. Haze occupied the central cornea, accompanied by corneal edema and neovascularization. In severe cases with marked chronic inflammation, a cell-fate switch from a transparent corneal epithelium to a keratinized, stratified squamous, psoriasiform-like epidermis was observed. The stroma contained a large number of CD11c, CD68, and CD3 positive cells. Corneal epithelial debridement experiments in young ACE2-deficient mice showed normal appearing corneas, devoid of haze. We hypothesized, however, that these mice are "primed" for a corneal inflammatory response, which once initiated, would persist. In vitro studies reveal that interleukins (IL-1a, IL-1b), chemokines (CCL2, CXCL8), and TNF-α, are all significantly elevated, resulting in a cytokine storm-like phenotype. This phenotype could be partially rescued by treatment with the AngII type 1 receptor (AT1R) antagonist, losartan, suggesting that the observed effect was mediated by AngII acting on its main receptor. Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes human ACE2 as the receptor for entry with subsequent downregulation of ACE2, corneal inflammation in Ace2 −/− mice may have a similar mechanism with that in COVID-19 patients. Thus the Ace2 −/− cornea, because of easy accessibility, may provide an attractive model to explore the molecular mechanisms, immunological changes, and treatment modalities in patients with COVID-19.

Vascular Endothelial Glycocalyx Damage in COVID-19

“…Activation of the S protein is important for the entry of the virus into cells by fusion of the viral outer membrane with the cell membrane. Furthermore, ACE2 deficiency, which could be induced by binding with SARS-CoV-2, is considered to drive a cytokine storm in patients with COVID-19 [ 19 ].…”

HDL Nanoparticles Have Wound Healing and Anti‐Inflammatory Properties and Can Topically Deliver miRNAs

“…Control NP treated corneas displayed a range of thickened and disorganized corneal epithelia as well as a wide spectrum of stromal alterations, ranging from a stroma filled with inflammatory cells (Figure 6C) to randomly oriented collagen bundles resulting in a disorganized appearance (Figure 6D). The infiltrates were identified as T cells by immunohistochemical (IHC) staining [ 53 ] for CD3 at day 7 (Figure S9, Supporting Information). In contrast, the HDL NP‐treated corneas showed well‐organized stratified epithelia (Figure 6E,F) and stroma with collagen bundles highly organized in a plywood‐like fashion that were relatively devoid of inflammatory cells (Figure 6E,F and Figure S8, Supporting Information).…”

Losartan promotes cell survival following SARS-CoV-2 infectionin vitro

“…Downregulation of ACE2 during the entry of the virus into the host cells leads to an increase in angiotensin II/angiotensin(1-7) ratio with proinflammatory, pro-apoptotic, destructive and pro-thrombotic effects [27, 46]. In animal studies, it was shown that ACE2 deficiency in mice and infusion of Ang II in swine resulted in corneal inflammatory response and lung pathology, respectively, resembling exactly the immunopathological changes seen in COVID-19 [47, 48]. In an in-silico study, Losartan was shown to change the tertiary structure of ACE2 in binding with receptor binding domain (RBD) of S protein of the virus as well as inducing modification in conformational shape of SARS-CoV-2 papain-like protease [27].…”