
-   In the context of inflammatory bowel disease (IBD), the production of S100A8 is limited by DOK3 suppressing JAK2/STAT3 signaling in colonic neutrophils, thereby maintaining gut microbial ecology and colon homeostasis. The data suggests that DOK3 maintains colonic neutrophils in a quiescent state to establish a gut microbiome essential for intestinal homeostasis and protection from IBD [PMID: 34743196].
-   Loss-of-function variants in the X-linked ETS transcription factor gene ELF4 was discovered in male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. In mouse macrophages, Elf4 both sustains the expression of anti-inflammatory genes, such as Il1rn, and limits the upregulation of inflammation amplifiers, including S100A8. ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD [PMID: 34326534].
-   The activation of Toll-like receptor 4 (TLR4) signaling promotes inflammation in colitis of mice, which may trigger the pathway that contains S100A8. Functional studies show that S100A8 increased the viability of colon cancer cell lines and decreased the apoptosis rate of colon cancer cells with irradiation and chemical treatment. The study associates S100A8 with the role of TLR4 in promoting spontaneous intestinal tumorigenesis [PMID: 31650683].
-   A functional genomics screen indicated that genes in four inflammatory bowel disease (IBD) GWAS loci (PTGIR, ZBTB40, SLC39A11 and NFKB1) are involved in controlling S100A8 and S100A9 gene expression, which encode the two subunits of calprotectin (CP). The data suggests a role for the PTGIR, PTGER4, ZBTB40, SLC39A11 and NFKB1 genes in IBD, with all five genes regulating the expression of CP in myeloid cells, as well as potential roles for the prostacyclin/prostaglandin biogenesis and signaling pathways in IBD susceptibility and pathogenesis [PMID: 36155972].

## Summary

S100A8 is involved in the regulation of inflammatory processes and immune response, particularly in the colon where it can induce neutrophil chemotaxis and adhesion [CS: 9]. In conditions like inflammatory bowel disease (IBD), the colon experiences chronic inflammation, leading to tissue damage and altered gut microbiota [CS: 9]. S100A8 responds to this inflammation by increasing the recruitment and adhesion of neutrophils to the inflamed areas [CS: 8]. This action is crucial for controlling the inflammation and initiating tissue repair [CS: 7]. Additionally, S100A8's role in antimicrobial activity becomes significant in the gut during colitis, where it helps in combating microbial infections by chelating zinc ions, essential for microbial growth [CS: 8]. This response is a defense mechanism to prevent further damage and to maintain intestinal integrity [CS: 8].

In cases of colon cancer, S100A8 expression is upregulated, which can be linked to its role in promoting inflammation, a known factor in tumorigenesis [CS: 8]. The protein contributes to the inflammatory microenvironment, which is conducive to cancer development [CS: 8]. S100A8's ability to activate the NADPH-oxidase complex also plays a role here, as this activation can lead to the production of reactive oxygen species (ROS), contributing to DNA damage and cancer progression [CS: 7].
