Imiquimod Boosts Interferon Response, and Decreases ACE2 and Pro-Inflammatory Response of Human Bronchial Epithelium in Asthma

• Published in: Frontiers in immunology Vol. 12; p. 743890
• Main Authors: Nieto-Fontarigo, Juan José, Tillgren, Sofia, Cerps, Samuel, Sverrild, Asger, Hvidtfeldt, Morten, Ramu, Sangeetha, Menzel, Mandy, Sander, Adam Frederik, Porsbjerg, Celeste, Uller, Lena
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.12.2021
• Subjects: Adjuvants, Immunologic - pharmacology; Adult; Aged; Angiotensin-Converting Enzyme 2 - metabolism; anti-viral drug; Asthma; Basic Medicine; Bronchi - drug effects; Bronchi - immunology; Bronchi - virology; Cells, Cultured; COVID-19; Female; Humans; imiquimod; Imiquimod - pharmacology; Immunologi inom det medicinska området; Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi); Immunology; Immunology in the medical area; Immunology in the Medical Area (including Cell and Immunotherapy); Interferon-beta - drug effects; Interferon-beta - immunology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - virology; SARS – CoV – 2; TLR7 agonist; COVID-19; SARS – CoV – 2; asthma; anti-viral drug; TLR7 agonist; imiquimod
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.743890

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 cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity. To investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients. 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. 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. 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.