ETAS(R)50 Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. ETAS(R)50, a standardized extract of Asparagus officinalis stem, is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide- and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of ETAS(R)50 on pro-inflammatory responses in S1-stimulated murine peritoneal exudate macrophages. Co-treatment of the cells with ETAS(R)50 significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. ETAS(R)50 also markedly suppressed the S1-induced transcription of IL-6 and IL-1{beta}. However, among the TLR4 signaling proteins, ETAS(R)50 did not affect the degradation of inhibitor {kappa}B, nuclear translocation of nuclear factor-{kappa}B p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, ETAS(R)50 significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1{beta} by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that ETAS(R)50 attenuates S1-induced IL-6 and IL-1{beta} production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, ETAS(R)50 may be beneficial in regulating excessive inflammation in patients with COVID-19.