| Autor: |
Wildenberg ME; Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Koelink PJ; Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands., Diederen K; Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands., Te Velde AA; Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Wolfkamp SC; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., Nuij VJ; Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands., Peppelenbosch MP; Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands., Nobis M; Beatson Institute for Cancer Research, Bearsden, Glasgow, UK., Sansom OJ; Beatson Institute for Cancer Research, Bearsden, Glasgow, UK., Anderson KI; Beatson Institute for Cancer Research, Bearsden, Glasgow, UK., van der Woude CJ; Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands., D'Haens GR; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands., van den Brink GR; Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. |
| Abstrakt: |
Thiopurines are commonly used drugs in the therapy of Crohn's disease, but unfortunately only show a 30% response rate. The biological basis for the thiopurine response is unclear, thus hampering patient selection prior to treatment. A genetic risk factor associated specifically with Crohn's disease is a variant in ATG16L1 that reduces autophagy. We have previously shown that autophagy is involved in dendritic cell (DC)-T-cell interactions and cytoskeletal regulation. Here we further investigated the role of autophagy in DC cytoskeletal modulation and cellular trafficking. Autophagy-deficient DC displayed loss of filopodia, altered podosome distribution, and increased membrane ruffling, all consistent with increased cellular adhesion. Consequently, autophagy-deficient DC showed reduced migration. The cytoskeletal aberrations were mediated through hyperactivation of Rac1, a known thiopurine target. Indeed thiopurines restored the migratory defects in autophagy-deficient DC. Clinically, the ATG16L1 risk variant associated with increased response to thiopurine treatment in patients with Crohn's disease but not ulcerative colitis. These results suggest that the association between ATG16L1 and Crohn's disease is mediated at least in part through Rac1 hyperactivation and subsequent defective DC migration. As this phenotype can be corrected using thiopurines, ATG16L1 genotyping may be useful in the identification of patients that will benefit most from thiopurine treatment. |
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