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.

Ken Shirato,Takako Kizaki,Jun Takanari

doi:10.3390/molecules26206189

Ken Shirato, Takako Kizaki + Show 1 more

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https://doi.org/10.3390/molecules26206189

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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.

Highlights

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a novel type of coronavirus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) strongly induces IL-6 and IL-1β production in murine and human macrophages by activating toll-like receptor 4 (TLR4) signaling, similar to the action of pyrogenic lipopolysaccharide (LPS) [14]
To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of extract of Asparagus officinalis stem (EAS) on pro-inflammatory responses in S1-stimulated murine primary macrophages

Summary

Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a novel type of coronavirus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Growing evidence suggests that excessive host inflammatory responses are associated with disease severity and mortality in patients [11,12]. Macrophages produce pro-inflammatory cytokines after detecting a broad range of pathogen-associated molecular patterns (PAMPs) using pattern recognition receptors, such as toll-like receptors (TLRs). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) strongly induces IL-6 and IL-1β production in murine and human macrophages by activating TLR4 signaling, similar to the action of pyrogenic lipopolysaccharide (LPS) [14]. Recent clinical studies suggest that the IL-6 receptor antagonists tocilizumab and sarilumab and the IL-1 receptor antagonist anakinra improve the survival of patients with COVID-19 [15,16]. Since the manifestation of inflammatory disorders is influenced by an individual’s lifestyle, it is important to explore functional foods as a prophylactic approach that can suppress excessive and undesired pro-inflammatory responses in macrophages

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