S100A8 Triggers Oxidation-sensitive Repulsion of Neutrophils

Abstract

The inflammatory response to tissue injury is a multi-faceted process. During this process, neutrophils migrate in the extravascular spaces, directed to the site of injury by chemical gradients generated by chemotactic molecules. S100A8, a protein associated with a wide variety of inflammatory conditions, is heavily over-expressed in association with inflammation. We hypothesized that human S100A8 possesses neutrophil-repelling properties that result in an antiinflammatory effect in vivo. The chemotactic activity of S100A8 on neutrophils was tested in Transwell chemotaxis assays. Analysis of the data indicates that S100A8 causes a repulsion of peripheral neutrophils, an activity that S100A8 loses upon its oxidation. Using a mutant of S100A8 resistant to oxidation and consistent with the in vitro findings, we demonstrated that S100A8 causes a strong anti-inflammatory effect in the rat air-pouch model of inflammation in vivo. These data highlight a naturally occurring novel anti-inflammatory pathway and provide potential molecular targets for the development of novel anti-inflammatory therapeutics.

Association among Vitamin D, Oral Candidiasis, and Calprotectinemia in HIV

“…In our previous work, we showed that calprotectin inhibits the recruitment of neutrophils and their oxidative metabolism (Sroussi et al, 2006(Sroussi et al, , 2010. It is tempting to speculate that vitamin D deficiency may therefore produce an exaggerated calprotectinemia which would then depress neutrophil responsiveness, contributing to a higher risk of OC.…”

Calgranulins May Contribute Vascular Protection In Atherogenesis

“…93 recruitment into the murine air-pouch in response to LPS, indicating antiinflammatory effects. 74 More recently, these investigators found that intravenous injection of S100A8/A9 into endotoxemic mice reduced neutrophil infiltration into organs; markers of oxidative damage decreased and survival rates doubled. The suggested mechanism was via S100A8 binding TLR4, an interaction that may interfere with protease-activated receptor-2 (PAR-2) cooperation with TLR4, to reduce the magnitude of inflammation.…”

“…67 The calgranulins have been reported to induce proinflammatory cytokines in monocytes/macrophages 68, 69 and are implicated in promoting EC adhesion and dysfunction, 70-72 and affecting SMC proliferation. 49, 73 However, S100A8 and S100A9 at physiological levels have neutrophil-repulsion activity, 74 and reduce the spontaneous and stimulated neutrophil oxidative burst, possibly mediated by adenosine metabolites. 75 The calgranulin receptors remain an enigma.…”

S-Nitrosylated S100A8: Novel Anti-Inflammatory Properties

“…S100A8 is a potent scavenger of peroxide and hypochlorite generated by activated neutrophils and macrophages (28,29). The chemotactic activity of murine (m)S100A8 is altered upon oxidation (28), and human (h)S100A8 has an anti-inflammatory, neutrophil-repelling property that is also oxidation sensitive (30).…”