Standardized Extract of Asparagus officinalis Stem 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

Abstract

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. A standardized extract of Asparagus officinalis stem (EAS) 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 EAS on pro-inflammatory responses in S1-stimulated macrophages. Murine peritoneal exudate macrophages were co-treated with EAS and S1. Concentrations and mRNA levels of pro-inflammatory cytokines were assessed using enzyme-linked immunosorbent assay and reverse transcription and real-time polymerase chain reaction, respectively. Expression and phosphorylation levels of signaling proteins were analyzed using western blotting and fluorescence immunomicroscopy. EAS significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. EAS also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, EAS did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, EAS 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-1β 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 EAS attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, EAS may be beneficial in regulating excessive inflammation in patients with COVID-19.

Cytokines and microRNAs in SARS-CoV-2: What do we know?

“…206 After recognizing a wide range of PAMPs via PRRs such as toll-like receptors (TLRs), macrophages generate pro-inflammatory cytokines. The SARS-CoV-2 spike protein S1 component substantially promotes IL-6 and IL-1b production in murine and human macrophages by activating TLR4 signaling via the JNK and NF-kB pathways, according to Shirato et al 207,208 In macrophages, the P44/42 MAPK and Akt pathways produce pro-inflammatory molecules.…”

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

“… 288 Extraction of Asparagus officinalis stem inhibits p44/42 MAPK and Akt signaling in macrophages and helps to alleviate excessive inflammation. 289 …”

“…Hydrogen ginger oleone (DHZ) regulates MAPK and NF‐κB pathways to inhibit CS, oxidation, and provide preclinical support for ARDS 288 . Extraction of Asparagus officinalis stem inhibits p44/42 MAPK and Akt signaling in macrophages and helps to alleviate excessive inflammation 289 …”

Dual quinoline-hybrid compounds with antimalarial activity against Plasmodium falciparum parasites

“…IL-1b promotes the attraction of granulocytes to the inflamed tissue and upregulates the expression of prostaglandins and other inflammatory mediators during the inflammatory response. 80 In addition, it is an important component of the host defense against infections, [81][82][83] and is increased in malaria-derived inflammation. 77,78 Despite the fact that chloroquine inhibited levels of TNF-a, IL-1b and IL-6 from Th1 and Th2 cells, its main role in the inflammatory process is through signaling, mitigating the pro-inflammatory effects because chloroquine suppressed IFN-g production and potently inhibited the differentiation of IFN-g-producing Th1 cells.…”