S100A12 in Digestive Diseases and Health: A Scoping Review

Abstract

Calgranulin proteins are an important class of molecules involved in innate immunity. These members of the S100 class of the EF-hand family of calcium-binding proteins have numerous cellular and antimicrobial functions. One protein in particular, S100A12 (also called EN-RAGE or calgranulin C), is highly abundant in neutrophils during acute inflammation and has been implicated in immune regulation. Structure-function analyses reveal that S100A12 has the capacity to bind calcium, zinc, and copper, processes that contribute to nutritional immunity against invading microbial pathogens. S100A12 is a ligand for the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and CD36, which promote cellular and immunological pathways to alter inflammation. We conducted a scoping review of the existing literature to define what is known about the association of S100A12 with digestive disease and health. Results suggest that S100A12 is implicated in gastroenteritis, necrotizing enterocolitis, gastritis, gastric cancer, Crohn's disease, irritable bowel syndrome, inflammatory bowel disease, and digestive tract cancers. Together, these results reveal S100A12 is an important molecule broadly associated with the pathogenesis of digestive diseases.

Figure 1

Model of S100A12 structure. (a) indicates PHYRE prediction of S100A12 secondary and tertiary structure. (b) indicates the primary structure beginning with helix 1 at the N terminus (pictured above in orange), calcium-binding loop 1 (pictured in yellow-orange), helix 2 (pictured in yellow), helix 3 (pictured in green), calcium-binding loop 2 (pictured in turquoise), and helix 4 (pictured in blue). The metal-binding residues which comprise the dimer interface are highlighted in red in the primary structure sequence. The two EF-hand motifs, similar in structure to a thumb and forefinger, are pictured in orange/yellow and green/blue, respectively. Metal-binding residues are highlighted in red.

Figure 2

Conceptual diagram of the association of S100A12 in various digestive diseases and health. S100A12 (EN-RAGE or calgranulin C, depicted in a dimer form) is produced by innate immune cells such as granulocytes and participates in the chemotaxis of innate immune cells. It can exist as a dimer or oligomer and can bind divalent cations including zinc, copper, and calcium to promote “nutritional immunity” against invading microbial pathogens. S100A12 interacts with cell surface membranes as well as RAGE, TLR4, and CD36 receptors to promote proinflammatory signaling and disease progression. S100A12 also interacts with CacyBP/SIP and S100A9. S100A12 binding of calcium and zinc enhances oligomerization and interactions with receptors such as RAGE.