TY - JOUR
T1 - The ACE2-deficient mouse
T2 - A model for a cytokine storm-driven inflammation
AU - Wang, Junyi
AU - Kaplan, Nihal
AU - Wysocki, Jan
AU - Yang, Wending
AU - Lu, Kurt
AU - Peng, Han
AU - Batlle, Daniel
AU - Lavker, Robert M.
N1 - Funding Information:
We are thankful to Amani A. Fawzi for her initial clinical evaluation of ACE2 KO eyes. The NU-SBDRC Skin Tissue Engineering and Morphology Core facility assisted in morphologic analysis. The NU-SBDRC Is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR075049. This research is supported by National Institutes of Health Grants EY06769, EY017539, and EY019463 (to RML); a Dermatology Foundation research grant and Career Development Award (to HP); an Eversight research grant (to HP), AR064144 and AR071168 (to KQL), an NIDDK grant R01DK104785 (to DB), and the International Postdoctoral Exchange Fellowship Program 20180087 (to J. Wang).
Funding Information:
We are thankful to Amani A. Fawzi for her initial clinical evaluation of ACE2 KO eyes. The NU‐SBDRC Skin Tissue Engineering and Morphology Core facility assisted in morphologic analysis. The NU‐SBDRC Is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR075049. This research is supported by National Institutes of Health Grants EY06769, EY017539, and EY019463 (to RML); a Dermatology Foundation research grant and Career Development Award (to HP); an Eversight research grant (to HP), AR064144 and AR071168 (to KQL), an NIDDK grant R01DK104785 (to DB), and the International Postdoctoral Exchange Fellowship Program 20180087 (to J. Wang).
Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - COVID-19
KW - SARS-CoV-2
KW - cornea
KW - corneal epithelial cells
KW - macrophages
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UR - http://www.scopus.com/inward/citedby.url?scp=85089285505&partnerID=8YFLogxK
U2 - 10.1096/fj.202001020R
DO - 10.1096/fj.202001020R
M3 - Article
C2 - 32725927
AN - SCOPUS:85089285505
VL - 34
SP - 10505
EP - 10515
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 8
ER -