Mast Cell and Monocyte Recruitment by S100A12 and Its Hinge Domain

Abstract

S100A12 is expressed at sites of acute, chronic, and allergic inflammation. S100 proteins have regions of high sequence homology, but the "hinge" region between the conserved calcium binding domains is structurally and functionally divergent. Because the murine S100A8 hinge domain (mS100A8 [42][43][44][45][46][47][48][49][50][51][52][53][54][55] ) is a monocyte chemoattractant whereas the human sequence (hS100A8 [43][44][45][46][47][48][49][50][51][52][53][54][55][56] ) is inactive, we postulated that common hydrophobic amino acids within the S100A12 hinge sequence may be functional. The hinge domain, S100A12 38 -53 , was chemotactic for human monocytes and murine mast cells in vitro. S100A12 38 -53 provoked an acute inflammatory response similar to that elicited by S100A12 in vivo and caused edema and leukocyte and mast cell recruitment. Circular dichroism studies showed that S100A12 38 -53 had increased helical structure in hydrophobic environments. Mutations in S100A12 38 -53 produced using an alanine scan confirmed that specific hydrophobic residues (I44A, I47A, and I53A) on the same face of the helix were critical for monocyte chemotaxis in vitro and generation of edema in vivo. In a hydrophobic environment such as the cell membrane, these critical residues would likely align on one face of an ␣-helix to facilitate receptor interaction. Interaction is unlikely to occur via the receptor for advanced glycation end products but, rather, via a G-protein-coupled mechanism.

Pleiotropic Roles of S100A12 in Coronary Atherosclerotic Plaque Formation and Rupture

“…S100A12 may play a pleiotropic role in atherogenesis. Our results indicate that S100A12 likely does not play a significant role in activating proinflammatory gene production in macrophages, although low concentrations are chemotactic for monocytes and mast cells (11) and may contribute to their accumulation. Higher levels may cause changes in the microcirculation by provoking mast cell activation (11) that potentiate atherogenesis (57).…”

“…Thus, S100A12 may modulate processes that contribute to atherogenesis. Some extracellular functions on monocytes/macrophages may be mediated by ligation of the receptor for advanced glycation end-products (RAGE) 3 (10), although our studies implicate additional receptors (9,11).…”

DAMPs and influenza virus infection in ageing

“…S100A8 and S100A9 are EF-hand Ca 2+ binding proteins which belong to the family of low molecular weight S100 proteins (10-13 kDa) consists of 22 members (Ravasi et al, 2004;Yan et al, 2008). The genes of S100A8 and A9 encode a pro-inflammatory protein known as calgranulin (Swindell et al, 2013).…”

Calgranulins May Contribute Vascular Protection In Atherogenesis

“…76 S100A8 and S100A9 functions may be dependent or independent of complex formation, whereas S100A8 and S100A12 chemotactic functions reside within the divergent hinge domains. 77 Affinity of S100A12 for the V domain of RAGE increases >1,000-fold in the Ca 2+ -78 or Zn 2+ -bound hexameric states. 79 Only S100A9 with Ca 2+ and Zn 2+ has high affinity for RAGE; S100A8 has virtually none, and S100A8/A9 binding is relatively weak.…”