S100A9 is a calcium- and zinc-binding protein which plays aprominent role in the regulation of inflammatory processes and immuneresponse. Itcan induce neutrophil chemotaxis, adhesion, can increase thebactericidal activity of neutrophils by promoting phagocytosis viaactivation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation ofneutrophils by a MAPK-dependent mechanism. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellularfunctions. Theintracellular functions include: facilitating leukocyte arachidonicacid trafficking and metabolism, modulation of the tubulin-dependentcytoskeleton during migration of phagocytes and activation of theneutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly atthe cell membrane, transferring arachidonic acid, an essentialcofactor, to the enzyme complex and S100A8 contributes to the enzymeassembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activityincludes recruitment of leukocytes, promotion of cytokine and chemokineproduction, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a dangerassociated molecular pattern (DAMP) molecule and stimulates innateimmune cells via 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 resulting in the amplificationof the pro-inflammatory cascade. Hasantimicrobial activity towards bacteria and fungi and exerts itsantimicrobial activity probably via chelation of Zn (2+) which isessential for microbial growth. Can induce cell deathvia autophagy and apoptosis and this occurs through the cross-talk ofmitochondria and lysosomes via reactive oxygen species (ROS) and theprocess involves BNIP3. Can regulate neutrophilnumber and apoptosis by an anti-apoptotic effect; regulates cellsurvival via ITGAM/ITGB and TLR4 and a signaling mechanism involvingMEK-ERK. Its role as an oxidant scavenger has aprotective role in preventing exaggerated tissue damage by scavengingoxidants. Can act as a potentamplifier of inflammation in autoimmunity as well as in cancerdevelopment and tumor spread. Has transnitrosylaseactivity; in oxidatively-modified low-densitity lipoprotein (LDL (ox) ) -induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer theNO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3. The iNOS-S100A8/A9 transnitrosylase complex isproposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM byrecognizing a [IL]-x-C-x-x-[DE] motif. [1-7]

MTCKMSQLERNIETIINTFHQYSVKLGHPDTLNQGEFKELVRKDLQNFLKKENKNEKVIEHIMEDLDTNADKQLSFEEFIMLMARLTWASHEKMHEGDEGPGHHHKPGLGEGTP