Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma
Nieto-Fontarigo, Juan José LU ; Tillgren, Sofia LU
; Cerps, Samuel
LU
; Sverrild, Asger
; Hvidtfeldt, Morten
; Ramu, Sangeetha
LU
; Menzel, Mandy
LU
; Sander, Adam Frederik
; Porsbjerg, Celeste
and Uller, Lena
LU
(2021)
In Frontiers in Immunology
12.
- Abstract
Background: Both anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity. Objective: To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients. Methods: Effects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of... (More)
Background: Both anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity. Objective: To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients. Methods: Effects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses. Results: Imiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections. Conclusion: Imiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.
(Less)
- author
- Nieto-Fontarigo, Juan José
LU
; Tillgren, Sofia
LU
; Cerps, Samuel
LU
; Sverrild, Asger
; Hvidtfeldt, Morten
; Ramu, Sangeetha
LU
; Menzel, Mandy
LU
; Sander, Adam Frederik
; Porsbjerg, Celeste
and Uller, Lena
LU
- organization
- publishing date
- 2021-12-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- anti-viral drug, asthma, COVID-19, imiquimod, SARS – CoV – 2, TLR7 agonist
- in
- Frontiers in Immunology
- volume
- 12
- article number
- 743890
- publisher
- Frontiers Media S. A.
- external identifiers
-
- pmid:34950134
- scopus:85121638235
- ISSN
- 1664-3224
- DOI
- 10.3389/fimmu.2021.743890
- language
- English
- LU publication?
- yes
- id
- fe6fb3b3-ff1b-4104-b7e5-980a3d540ac8
- date added to LUP
- 2022-02-04 12:57:59
- date last changed
- 2025-01-03 13:41:57
@article{fe6fb3b3-ff1b-4104-b7e5-980a3d540ac8,
abstract = {{<p>Background: Both anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity. Objective: To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients. Methods: Effects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses. Results: Imiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections. Conclusion: Imiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.</p>}},
author = {{Nieto-Fontarigo, Juan José and Tillgren, Sofia and Cerps, Samuel and Sverrild, Asger and Hvidtfeldt, Morten and Ramu, Sangeetha and Menzel, Mandy and Sander, Adam Frederik and Porsbjerg, Celeste and Uller, Lena}},
issn = {{1664-3224}},
keywords = {{anti-viral drug; asthma; COVID-19; imiquimod; SARS – CoV – 2; TLR7 agonist}},
language = {{eng}},
month = {{12}},
publisher = {{Frontiers Media S. A.}},
series = {{Frontiers in Immunology}},
title = {{Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma}},
url = {{http://dx.doi.org/10.3389/fimmu.2021.743890}},
doi = {{10.3389/fimmu.2021.743890}},
volume = {{12}},
year = {{2021}},
}