Abstract
Background. Clinical and experimental evidence point to a dysregulated immune response caused by SARS-CoV-2 as the primary mechanism of lung disease in COVID-19. However, the pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. This study aims to explore the inflammatory responses of alveolar epithelial cells to either the spike S1 protein or to a mixture of cytokines secreted by S1-activated macrophages. Methods and Results. The exposure of alveolar A549 cells to supernatants from spike-activated macrophages caused a further release of inflammatory mediators, with IL-8 reaching massive concentrations. The investigation of the molecular pathways indicated that NF-kB is involved in the transcription of IP-10 and RANTES, while STATs drive the expression of all the cytokines/chemokines tested, with the exception of IL-8 which is regulated by AP-1. Cytokines/chemokines produced by spike-activated macrophages are also likely responsible for the observed dysfunction of barrier integrity in Human Alveolar Epithelial Lentivirus-immortalized cells (hAELVi), as demonstrated by an increased permeability of the monolayers to mannitol, a marked decrease of TEER and a disorganization of claudin-7 distribution. Conclusion. Upon exposure to supernatants from S1-activated macrophages, A549 cells act both as targets and sources of cytokines/chemokines, suggesting that alveolar epithelium along with activated macrophages may orchestrate lung inflammation and contribute to alveolar injury, a hallmark of ARDS.
Highlights
Published: 7 March 2022Coronavirus disease-2019 (COVID-19) is a highly infectious respiratory syndrome caused by the new coronavirus SARS-CoV-2 (Severe Acute Respiratory SyndromeCoronavirus-2) [1,2], that primarily causes infection in the respiratory tract
The inflammatory profile of A549 cells was evaluated after the direct treatment with S1, as well as upon incubation with the conditioned medium obtained from human macrophages incubated for 16 h in the presence of S1 (CM_S1)
Huge increases of mRNA levels for all the inflammatory mediators were observed when cells were incubated for 5 h with conditioned medium from S1-treated macrophages (CM_S1), pointing to the existence of immunemediated inflammatory effects (Figure 1B)
Summary
Coronavirus disease-2019 (COVID-19) is a highly infectious respiratory syndrome caused by the new coronavirus SARS-CoV-2 (Severe Acute Respiratory SyndromeCoronavirus-2) [1,2], that primarily causes infection in the respiratory tract. ARDS is characterized by an acute and diffuse inflammatory damage into the alveolarcapillary barrier associated with an increase of vascular permeability that causes alveolar oedema, leading to hypoxia. The reason for this wide spectrum of manifestations associated with the infection by the same virus is still unclear. The pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. The exposure of alveolar A549 cells to supernatants from spike-activated macrophages caused a further release of inflammatory mediators, with.
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