Abstract
Staphylococcus aureus inhibits complement activity by secreting a variety of toxins. However, the underlying mechanism of complement component regulation by lipoteichoic acid (LTA), a cell wall component of S. aureus, has not been elucidated. In this study, we observed that aLTA (LTA of S. aureus) increased C3 expression in THP-1 cells. The mechanism of aLTA-mediated C3 induction includes an aLTA-toll-like receptor (TLR) 2 interaction, interleukin 1 receptor associated kinase (IRAK) 2 recruitment, and nuclear factor kappa B (NF-kB) activation. In HepG2 cells, C3 protein production begins to increase from 3 h and increases steadily until 48 h. On the other hand, CD55 levels increased up to 6 h after aLTA treatment and started to decrease after 24 h and levels were decreased at 48 h by more than 50% compared to untreated cells. The expression of CD55 in HepG2 cells was shown to be regulated by IRAK-M induced by aLTA. Serum C3 levels increased in mice injected with aLTA, which resulted in an increase in the amount and activity of the membrane attack complex (MAC). We also observed that CD55 mRNA was increased in the liver 24 h after aLTA injection, but was decreased 48 h after injection. These results suggest that aLTA increases complement levels via induction of C3 and inhibition of CD55, which may cause associated MAC-mediated liver damage.
Highlights
Accepted: 20 May 2021Staphylococcus aureus is a Gram-positive bacterium that is often found in the nose, respiratory system, and on the skin
Complement is part of the innate immune system [2] that is activated by three routes including the classic, lectin, and alternative pathways and can detect and opsonize S. aureus to promote its phagocytosis by neutrophils in the blood and macrophages in tissues
When THP-1 cells were treated with aureus LTA (aLTA) for 6 h, C3 messenger RNA (mRNA) was increased by 18-fold as compared to the untreated cells
Summary
Staphylococcus aureus is a Gram-positive bacterium that is often found in the nose, respiratory system, and on the skin. Complement is part of the innate immune system [2] that is activated by three routes including the classic, lectin, and alternative pathways and can detect and opsonize S. aureus to promote its phagocytosis by neutrophils in the blood and macrophages in tissues. Extracellular fibrinogen-binding protein (Efb) produced by S. aureus can bind to the alpha chain of C3 and inhibit both the classical and alternative pathways of complement activation [6]. The tissue-resident macrophages in the liver, are able to capture circulating S. aureus through recognition of LTA by the complement receptor of immunoglobulin superfamily [9]. The mechanism of complement C3 expression regulation and complement activity by S. aureus LTA (aLTA) is not well known. We sought to elucidate the mechanism of C3 induction and CD55 inhibition in aLTA-treated THP-1 and HepG2 cells, respectively, and changes in complement activity by aLTA were observed in mice
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