Fecal Detection of Calprotectin Subunits Links Inflammatory Bowel Disease Activity With Chronicity of Intestinal Inflammation.
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Jukic Almina, Hilbe Richard, Zundel Luis, Willeit Peter, Faserl Klaus, Plattner Christina, Zollner Andreas, Meyer Moritz, Siegmund Kerstin, Klepsch Victoria, Marteau Valentin, Vich Vila Arnau, Schwärzler Julian, Vouk Kathrin, Kozsar Anna, Rieder Dietmar, Weichberger Amos, Sarg Bettina, Grabherr Felix, Mayr Lisa, Moser Patrizia, Nemati Niloofar, Scholl-Bürgi Sabine, Karall Daniela, Vogel Georg F, Welz Lina, Aldrian Denise, Koch Robert, Pfister Alexandra, Ran Qitao, Kaser Arthur, Blumberg Richard S, Tancevski Ivan, Sommer Felix, Bacher Petra, Schreiber Stefan, Rosenstiel Philip, Aden Konrad, Baier Gottfried, Bakiri Latifa, Müller Thomas, Weiss Günter, TRR241 IBDome Consortium, Weersma Rinse K, Trajanoski Zlatko, Wagner Erwin F, Tilg Herbert, Adolph Timon E
Аннотация
METHODS: We dissected fecal S100A8 and S100A9 configurations in patients with IBD by size-exclusion chromatography coupled with tandem mass spectrometry and systematically defined human S100A8 and S100A9 homodimer functions compared with the calprotectin heterotetramer (CP) in the intestine of mice and in human epithelium and T cells. Moreover, we report a protein interaction network of fecal S100A8 and S100A9 in IBD.
RESULTS: Stool from patients with active IBD contained abundant S100A8 and S100A9 dimers besides CP. Fecal S100A9 detection associated with clinical and endoscopic disease activity in IBD patients with low CP concentration. Oral exposure to human recombinant S100A8 and S100A9 homodimers, but not to CP, worsened intestinal inflammation in toxic and genetic mouse models. Functional profiling revealed that human S100A8 and S100A9 homodimers enhanced activation of cluster of differentiation 4+ and 8+ T cells, which promoted experimental colitis. In turn, genetic inactivation of S100a9 protected against experimental enteritis and colitis, and pharmacologic inhibition of S100A9 ameliorated chronic colitis.
CONCLUSIONS: Collectively, this study links the detection of fecal S100A9 dimers with clinical and endoscopic disease activity in IBD and identifies inflammatory actions of S100A8 and S100A9 homodimers in the intestine. Our findings pave the way for novel diagnostic and therapeutic approaches in patients with inflammatory diseases of the intestine.