The roles of toll-like receptor 4, CD33, CD68, CD69, or CD147/EMMPRIN for monocyte activation by the DAMP S100A8/S100A9

Abstract

The S100A8/A9 heterocomplex is an abundant damage-associated molecular pattern and mainly expressed by monocytes, inflammatory activated keratinocytes and neutrophilic granulocytes. The heterocomplex as well as the heterotetramer are involved in a variety of diseases and tumorous processes. However, their detailed mode of action and especially which receptors are involved hereby remains to be fully revealed. Several cell surface receptors are reported to interact with S100A8 and/or S100A9, the best studied being the pattern recognition receptor TLR4. RAGE, CD33, CD68, CD69, and CD147, all of them are involved as receptors in various inflammatory processes, are also among these putative binding partners for S100A8 and S100A9. Interactions between S100 proteins and these receptors described so far come from a wide variety of cell culture systems but their biological relevance in vivo for the inflammatory response of myeloid immune cells is not yet clear. In this study, we compared the effect of CRISPR/Cas9 mediated targeted deletion of CD33, CD68, CD69, and CD147 in ER-Hoxb8 monocytes on S100A8 or S100A9 induced cytokine release with TLR4 knockout monocytes. Whereas deletion of TLR4 abolished the S100-induced inflammatory response in monocyte stimulation experiments with both S100A8 and S100A9, knockouts of CD33, CD68, CD69, or CD147 revealed no effect on the cytokine response in monocytes. Thus, TLR4 is the dominant receptor for S100-triggered inflammatory activation of monocytes.

Interaction of S100A6 Protein with the Four-Helical Cytokines

“…Despite the lack of a leader sequence, some of the S100 proteins are secreted via the endoplasmic reticulum (ER)/Golgi pathway, or several unconventional passive and active mechanisms [ 2 , 27 , 28 ]. When they are released into the extracellular space, certain S100 proteins exert a cytokine-like action, due to interaction with specific cell surface receptors, such as RAGE, TLR4, ErbB1, ErbB3, ErbB4, IL-10R, integrin β1, neuroplastin-β, 5-HT 1B , 4-HT 4 , SIRL-1, ALCAM, EMMPRIN, CD33, CD36, CD68, CD69, or CD146 [ 2 , 25 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Moreover, some of the released S100 proteins interact with cytokines.…”

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts

“…It has been reported that S100A8 acts as a ligand that binds to the CD147 receptor, thereby regulating various cell fates. 47 , 48 , 49 Likewise, ligand-receptor interaction analysis between cancer cells and myCAFs indicated stronger interaction of S100A8 with the CD147 receptor compared to other receptors ( Figure S4 B). In this study, we generated CD147-knockout CAFs using CRISPR-Cas9-mediated gene targeting, in which CD147 deletion significantly suppressed the expression of αSMA ( Figure 4 H).…”

An aging-related immune landscape in the hematopoietic immune system

“…Next, we sought to determine whether classical inflammatory and immune response-related genes were regulated by aging in a cell type-specific manner. Upset diagrams integrating the up-regulated DEGs in B cell subsets of old mice showed that the inflammatory response-related genes Igha and S100a8 were up-regulated in all B cells [ 24 , 25 ]. The immune system signaling pathway-related genes Irf8 and Zeb2 [ 26 ] were upregulated in ABC (Fig.…”