Calcium and zinc tune autoinflammatory Toll-like receptor 4 signaling by S100A12

Abstract

This study was supported by grants from the intramural innovative medical research program of Muenster University medical faculty (grant no. KE121201 to C.K.) and the German Research Foundation (DFG, grant no. WI3176/2-1 to H.W. and grant no. Fo354/3-1 to D.F.). Disclosure of potential conflict of interest: C. Kessel & D. Foell have filed a patent application on ''means and methods for diagnosing and treating inflammatory disorders'' regarding proinflammatory S100A12 homomultimers (WO 2016/178154 A1). The rest of the authors declare that they have no relevant conflicts of interests.

Monocyte‐Derived Interleukin‐1β As the Driver of S100A12‐Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Disease

“…On the other hand, a study by Stoll et al also confirmed TLR‐4 expression on coronary artery endothelial cells, both in vitro and by immunostaining of tissue . In a parallel study of human monocytes performed by us, we noted that CD14 serves as a coreceptor to TLR‐4 with an integral role in S100A12 signaling . While the present data support these findings, they further suggest that S100A12 signaling in the absence of membrane CD14 cannot be bypassed by the soluble form of the receptor.…”

“…To determine whether the muted response of HCAECs to LPS and S100A12 was attributable to lower expression of TLR‐4 coreceptors, we measured the expression of CD14 both on primary human monocytes and on HCAECs, since detection of TLR‐4 agonists can involve the interaction of TLR‐4 with CD14 . As expected, our results showed that HCAECs expressed significantly lower levels of TLR‐4 compared to that in human monocytes (Figure B).…”

“…However, in our initial experiments, we stimulated HCAECs by supernatant transfer or coculture with S100A12‐stimulated PBMCs. It is known that human monocytes, as is present, for example, in PBMC preparations, respond well to S100A12 stimulation . Increased numbers of peripheral blood CD14+CD16+ monocytes have been observed in the serum of patients with KD , and monocytes have been found to be associated with endothelial cell dysfunction in patients with coronary artery disease .…”

“…When released from human granulocytes, S100A12 can operate as a damage‐associated molecular pattern (DAMP) molecule. In this role, it can mediate proinflammatory cellular responses via pattern‐recognition receptors (PRRs), namely the receptor of glycation end products (RAGE) or Toll‐like receptor 4 (TLR‐4) . The PRR that induces a cellular response to S100A12 may be dictated by cell type.…”

“…For example, transgenic expression of S100A12 in murine vascular smooth muscle cells (VSMCs) promotes aortic wall remodeling and aortic aneurysms in a RAGE‐dependent manner . Conversely, RAGE on human monocytes can engage S100A12, but cellular responsiveness is strictly TLR‐4 dependent .…”