S100A8/A9 in Inflammation

Abstract

S100A8 and S100A9 (also known as MRP8 and MRP14, respectively) are Ca²⁺ binding proteins belonging to the S100 family. They often exist in the form of heterodimer, while homodimer exists very little because of the stability. S100A8/A9 is constitutively expressed in neutrophils and monocytes as a Ca²⁺ sensor, participating in cytoskeleton rearrangement and arachidonic acid metabolism. During inflammation, S100A8/A9 is released actively and exerts a critical role in modulating the inflammatory response by stimulating leukocyte recruitment and inducing cytokine secretion. S100A8/A9 serves as a candidate biomarker for diagnosis and follow-up as well as a predictive indicator of therapeutic responses to inflammation-associated diseases. As blockade of S100A8/A9 activity using small-molecule inhibitors or antibodies improves pathological conditions in murine models, the heterodimer has potential as a therapeutic target. In this review, we provide a comprehensive and detailed overview of the distribution and biological functions of S100A8/A9 and highlight its application as a diagnostic and therapeutic target in inflammation-associated diseases.

Keywords: S100A8; S100A9; biomarker; infection; inflammation.

Figure 1

The binding of S100A8/A9 to toll-like receptor (TLR) 4 triggers the MyD88-dependent pathway, appearing to play a vital role in inflammation. MyD88 recruits and activates IRAKs and TRAF6, which activates TAK1 via a TAB-mediated method. The activation of TAK1 facilitates the phosphorylation and activation of IKK and MAPK. Activated IKK phosphorylates and ubiquitinates I-κB, resulting in the liberation of NF-κB from inhibition. NF-κB translocates to the nucleus and induces the expression of pro-inflammatory cytokines. MAPKs, including p38, JNK, and ERK, have been demonstrated to activate c-Jun and c-fos, which translocate to the nucleus and form heterodimer AP-1, another transcription factor. Moreover, MAPK pathways are also involved in S100A8/A9-induced NF-κB activation during inflammation. The upregulated expression of pro-inflammatory genes amplifies the inflammatory response and severely destructs tissues in inflammation-associated diseases.

Figure 2

The mitochondrial pathways of S100A8/A9-induced apoptosis. Cellular apoptosis is a cascade that involves a rapid drop in mitochondrial membrane potential. S100A8/A9 increases reactive oxygen species (ROS) production, resulting in the depolarization of mitochondrial membranes and subsequent inhibition of BNIP3, an atypical pro-apoptotic Bcl2-family member, and activation of Bak. After the translocation of Bak and BNIP3 in mitochondria, cytochrome C, Smac, and HtrA2 are concomitantly released from mitochondria into the cytoplasm. They activate caspase-3 in a direct way or in an IAPs-dependent manner to induce apoptosis. Abbreviations: iBNIP3, inhibited BNIP3; aBak, activated Bak.