Function
S100A8 is a calcium- and zinc-binding protein that plays a significant role in regulating inflammatory processes and immune responses. It can induce neutrophil chemotaxis and adhesion. Primarily found as calprotectin (S100A8/A9), it exhibits a wide range of intra- and extracellular functions.
Intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulating the tubulin-dependent cytoskeleton during phagocyte migration, and activating neutrophilic NADPH-oxidase. S100A8 activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid (an essential cofactor) to the enzyme complex, and directly binding to NCF2/P67PHOX, contributing to enzyme assembly.
Extracellular functions encompass proinflammatory, antimicrobial, oxidant-scavenging, and apoptosis-inducing activities. Its proinflammatory activity involves leukocyte recruitment, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. S100A8 acts as an alarmin or a danger-associated molecular pattern (DAMP) molecule, stimulating innate immune cells by binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways, amplifying the proinflammatory cascade.
S100A8 exhibits antimicrobial activity against bacteria and fungi, likely through chelation of Zn(2+), an essential nutrient for microbial growth. It can induce cell death via autophagy and apoptosis, involving cross-talk between mitochondria and lysosomes via reactive oxygen species (ROS), and the process includes BNIP3. S100A8 regulates neutrophil number and apoptosis by an anti-apoptotic effect, influencing cell survival through ITGAM/ITGB and TLR4 via a signaling mechanism involving MEK-ERK.
Its role as an oxidant scavenger provides protection by preventing excessive tissue damage through the removal of oxidants. S100A8 can act as a potent amplifier of inflammation in autoimmune disorders and cancer development and spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and potentially multiple targets such as ANXA5, EZR, MSN, and VIM by recognizing a [IL]-x-C-x-x-[DE] motif. S100A8 appears to contribute to S-nitrosylation site selectivity.
Upon infection by human coronavirus SARS-CoV-2, S100A8 may induce the expansion of aberrant immature neutrophils in a TLR4-dependent manner.