S100A8 triggers oxidation-sensitive repulsion of neutrophils.
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 anti-inflammatory 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. Abbrevations: ethylene diamine tetraacetic acid (EDTA); limulus amoebocyte lysate assay (LAL); pertussis toxin (PTX); forward scatter (FSC); Interleukin-8 (IL-8); formyl-Met-Leu-Phe (fMLP); monocyte chemotactic protein 1 (MCP1).
Sroussi
H Y
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Department of Oral Medicine and Diagnostic Sciences, University of Illinois at Chicago, College of Dentistry (M/C 838), 801 S. Paulina St., Room 556, Chicago, IL 60612-7213, USA. sroussih@uic.edu
Berline
J
J
Dazin
P
P
Green
P
P
Palefsky
J M
JM
D000409:Alanine / Q000378:metabolism; D000818:Animals; D040501:Calgranulin A / Q000502:physiology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D003545:Cysteine / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D040501:Calgranulin A; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003545:Cysteine; D000409:Alanine