ACE2 expression and spike S1 protein‐mediated immune responses in oral mucosal cells

• Published in: Oral diseases 2024-05, Vol.30 (4), p.2293-2305
• Main Authors: Akagi, Misaki, Ohta, Kouji, Fukada, Shohei, Sakuma, Miyuki, Naruse, Takako, Nakagawa, Takayuki, Ono, Shigehiro, Nishi, Hiromi, Shigeishi, Hideo, Aikawa, Tomonao
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Cell Line; Chemokine CXCL10 - metabolism; CXCL10 protein; Cytokines; Cytokines - metabolism; Fibroblasts - immunology; Fibroblasts - metabolism; Gene expression; Humans; Immune response; Infections; Inflammation; Keratinocytes; Keratinocytes - immunology; Keratinocytes - metabolism; Mouth Mucosa - immunology; Mucosal immunity; Nucleotides; Oral cancer; oral fibroblasts; oral keratinocytes; Polyinosinic:polycytidylic acid; Proteins; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; spike S1 protein; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1354-523X; 1601-0825; 1601-0825
• DOI: 10.1111/odi.14670

Objectives ACE2, known as a host receptor involved with SARS‐CoV‐2 infection, binds to viral spike proteins for host cell entry. However, details regarding its induction and function in oral mucosal cells remain unknown. Materials and Methods We examined ACE2 expression and its induction by transfected mimic nucleotides and pro‐inflammatory cytokines in oral keratinocytes (RT7) and fibroblasts (GT1). Subsequently, the effects of viral spike S1 protein via ACE2 on CXCL10 expression induced by pro‐inflammatory cytokines in both cells were examined. Results ACE2 was constitutively expressed in RT7 and GT1. Transfected Poly(I:C) and Poly(dA:dT) increased ACE2 expression in those cells, while knockdown of RIG‐I decreased ACE2 expression induced by those transfected ds nucleotides. IFN‐γ and TNF‐α enhanced transfected ds nucleotides‐induced ACE2 expression in RT7 but not GT1. S1 protein alone did not affect CXCL10 expression in either cell type, whereas it enhanced IFN‐β‐induced CXCL10 in both, while immune responses of IFN‐γ‐ and TNF‐α‐induced CXCL10 enhanced by S1 protein were different between RT7 and GT1. Finally, knockdown of ACE2 decreased cytokines and S1 protein mediated‐CXCL10 levels in both cells. Conclusions ACE2 in oral mucosal cells may contribute to development of infection and inflammation in cooperation with pro‐inflammatory cytokines following SARS‐CoV‐2 invasion.