Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically changed our world, country, communities, and families. There is controversy regarding risk factors for severe COVID-19 disease. It has been suggested that asthma and allergy are not highly represented as comorbid conditions associated with COVID-19.

Objective: Our aim was to extend our work in IL-13 biology to determine whether airway epithelial cell expression of 2 key mediators critical for SARS-CoV-2 infection, namely, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), are modulated by IL-13.

Methods: We determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. We also examined expression of ACE2 and TMPRSS2 in 2 data sets containing gene expression data from nasal and airway epithelial cells from children and adults with asthma and allergic rhinitis.

Results: IL-13 significantly reduced ACE2 and increased TMPRSS2 expression ex vivo in airway epithelial cells. In 2 independent data sets, ACE2 expression was significantly reduced and TMPRSS2 expression was significantly increased in the nasal and airway epithelial cells in type 2 asthma and allergic rhinitis. ACE2 expression was significantly negatively associated with type 2 cytokines, whereas TMPRSS2 expression was significantly positively associated with type 2 cytokines.

Conclusion: IL-13 modulates ACE2 and TMPRSS2 expression in airway epithelial cells in asthma and atopy. This deserves further study with regard to any effects that asthma and atopy may render in the setting of COVID-19 infection.

Keywords: ACE2; Asthma; COVID-19; IL-13; SARS-CoV-2; TMPRSS2; airway epithelial cells; nasal epithelial cells; type 2 inflammation.

Fig 1

IL-13 exposure reduces ACE2 and increases TMPRSS2 expression in airway epithelial cells from participants with asthma and atopy. A, IL-13 exposure significantly reduces ACE2 expression in nonasthma atopic (mean = 1.27 [95% CI = 1.05-1.54] vs mean = 0.62 [95% CI 0.54-0.71]; ∗P = .0001) and asthmatic (mean = 0.95 [95% CI = 0.77-1.17] vs mean = 0.47 [95% CI = 0.27-0.82]; ^†P = .038) airway epithelial cells. B, IL-13 significantly increases TMPRSS2 expression in nonasthma atopic (mean = 0.69 [95% CI = 0.62-0.77] vs mean = 1.16 [95% CI = 1.10-1.23]; ∗P < .0001) and asthmatic (mean = 0.58 [95% CI 0.55-0.61] vs mean 1.28 [95% CI 1.15-1.44]; †P < .0001) airway epithelial cells.

Fig 2

ACE2 expression is reduced in nasal epithelial cells from type 2 (T2)-high participants with allergy. A, In data set GSE19187, participants with asthma and allergic rhinitis demonstrate lower expression of ACE2. ∗P = .0039. B, Participants with uncontrolled asthma (UA) demonstrate lower ACE2 expression than healthy controls do. ∗P = .0053 for the paired comparison; ^†P = .0035. C, When subtyped to T2-low and T2-high groups, T2-high participants demonstrate lower ACE2 expression than healthy controls do. ∗P = .0024 for paired comparison. Box plots show medians with interquartile ranges. CA, Rhinitis with controlled asthma; NA, rhinitis without asthma; UA, rhinitis with uncontrolled asthma.

Fig 3

ACE2 expression is significantly negatively correlated with IL-13 expression. The data from GSE19187 reveal no significant correlation between IL-4 and ACE2(A) and between IL-5 and ACE2(B). (C)IL-13 and ACE2 are significantly negatively correlated when all groups are combined. r_s, Spearman rank correlation coefficient.

Fig 4

ACE2 expression is decreased in airway epithelial cells in type 2 (T2)-high asthma. A, In the gene expression data set from adult participants in GSE4302, ACE2 expression is reduced in all asthma participants compared with in healthy participants, with a trend toward significance (P = .097). B, Patients with T2-high asthma demonstrate lower airway epithelial ACE2 expression than healthy participants do. ∗P = .031 for the paired comparison. Box plots show medians with interquartile ranges.

Fig 5

Airway epithelial ACE2 is significantly negatively correlated with expression of IL-4, IL-5, and IL-13. Analysis of data set GSE4302 reveals a significant negative correlation of IL-4, IL-5, and IL-13 with ACE2 in the airway epithelial cells from participants with asthma and when asthma and healthy groups are combined. r_s, Spearman rank correlation coefficient.

Fig 6

TMPRSS2 gene expression is higher in nasal epithelial cells from type 2 (T2)-high participants with allergy. In data set GSE19187, participants with asthma and/or allergic rhinitis demonstrate increased nasal epithelial expression of TMPRSS2 compared with that demonstrated by healthy participants regardless of whether the allergy and asthma groups were combined (∗P = .0022) (A) or evaluated as separate groups (∗P = .018 for the paired comparison; ^†P = .034) (B). C, The T2-high participants demonstrate significantly higher expression of TMPRSS2, whereas the expression of TMPRSS2 by T2-low participants is similar to that demonstrated by healthy participants. ∗P = .0012 for the paired comparison. Box plots show medians with interquartile ranges. CA, Rhinitis with controlled asthma; NA, rhinitis and no asthma; UA, rhinitis with uncontrolled asthma.

Fig 7

TMPRSS2 expression is higher in the airway epithelial cells from type 2 (T2)-high asthma, with a trend toward significance. A, In the adult asthma study GSE4302, TMPRSS2 expression is not significantly different between healthy participants and participants with asthma (P = .13). B,TMPRSS2 expression tended to be higher in T2-high participants with asthma than in healthy participants (P = .086). Box plots show medians with interquartile ranges.

Fig E1

Expression of ACE2 and the type 2 (T2)-driven genes CLCA1 and SERPINB2 is significantly inversely correlated in nasal epithelial cells. Analysis of gene expression data from data set GSE19187 reveals inverse correlations between ACE2 with the T2-driven genes CLCA1(A), POSTN(B), and SERPINB2(C), with SERPINB2 trending toward significance. r_s, Spearman rank correlation coefficient.

Fig E2

ACE2 and type 2 (T2)-driven genes are inversely correlated in airway epithelial cells. In data set GSE4302 from adult participants with asthma and healthy controls, ACE2 is inversely correlated with CLCA1 (A), POSTN (B), and SERPINB2 (C) when asthma and control groups are combined, with POSTN trending toward significance. r_s: Spearman rank correlation coefficient.

Fig E3

TMPRSS2 expression is significantly correlated with type 2 (T2)-related genes in nasal epithelial cells. When the data set GSE19187 is used, significantly positive correlations between TMPRSS2 and the T2-driven signature genes CLCA1, POSTN, and SERPINB2 are present, but no such correlations are present with the T2 cytokines IL-4, IL-5, and IL-13. r_s, Spearman rank correlation coefficient.

Fig E4

Airway epithelial TMPRSS2 expression is significantly positively correlated with IL-4 expression. Data from GSE4302 revealed a significant correlation between airway epithelial TMPRSS2 expression and IL-4 when both groups are combined and for asthma only (A). B and C, This relationship is not demonstrated for IL-5 and IL-13. r_s, Spearman rank correlation coefficient.

Fig E5

TMPRSS2 and type 2 (T2)-driven genes are significantly positively correlated in airway epithelial cells. In data set GSE4302, airway epithelial cell TMPRSS2 expression is significantly positively correlated with expression of CLCA1 (A) and SERPINB2 (C) but not with expression of POSTN (B) when asthma and healthy control groups are combined. r_s, Spearman rank correlation coefficient.