title: Calgranulins may contribute vascular protection in atherogenesis.
abstract: S100A8, S100A9 and S100A12 are considered proinflammatory mediators of atherosclerosis. Known as calgranulins, they are major components of neutrophils and are upregulated in macrophages and foam cells. They influence leukocyte recruitment, and may propagate inflammation by binding TLR4 and/or receptor for advanced glycation endproducts (RAGE). However, the receptors for calgranulins remain an enigma; we have no evidence for TLR4 or RAGE activation by S100A8 or S100A12. Moreover, gene regulation studies suggest antiinflammatory functions for S100A8 and emerging reports indicate pleiotropic roles. Unlike S100A9, S100A8 effectively scavenges oxidants generated by the myeloperoxidase system in vivo, forming novel thiol modifications. S100A8 is also readily S-nitrosylated, stabilizing nitric oxide and transporting it to hemoglobin. S100A8-SNO reduces leukocyte transmigration in the vasculature. S-glutathionylation of S100A9 modifies its effects on leukocyte adhesion. Both S100A8 forms inhibit mast cell activation, at least partially by scavenging reactive oxygen species required for signaling. Conversely, S100A12 activates and sequesters mast cells. However S100A12 suppresses proinflammatory cytokine induction by SAA-activated monocytes and macrophages, and inhibits matrix metalloprotease activity. We propose that the abundance and types of cells expressing calgranulins in particular microenvironments, their relative concentrations and post-translational modifications may have distinct functional outcomes, including those that are protective, at different stages of atherogenesis.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Geczy
authors.forename: Yuen Ming
authors.initials: YM
authors.lastname: Chung
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hiroshima
mesh_terms: D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000378:metabolism*; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D039841:Leukocyte L1 Antigen Complex; D016877:Oxidants; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D009195:Peroxidase