title: The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines.
abstract: 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.
authors.affiliation: Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Wildenberg
authors.affiliation: Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Koelink
authors.affiliation: Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Diederen
authors.affiliation: Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: A A
authors.initials: AA
authors.lastname: Te Velde
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: S C S
authors.initials: SC
authors.lastname: Wolfkamp
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: V J
authors.initials: VJ
authors.lastname: Nuij
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
authors.forename: M
authors.initials: M
authors.lastname: Nobis
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
authors.forename: K I
authors.initials: KI
authors.lastname: Anderson
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: van der Woude
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G R A M
authors.initials: GR
authors.lastname: D'Haens
authors.affiliation: Tytgat Institute for Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000483:Alleles; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism*; D021961:Cell Membrane Structures / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D003599:Cytoskeleton / Q000378:metabolism; D003713:Dendritic Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015122:Mercaptopurine / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012306:Risk; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D034741:RNA, Small Interfering; D015122:Mercaptopurine; D020830:rac1 GTP-Binding Protein