The ATG16L1 risk allele associated with Crohn's disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines

Mucosal Immunology

Volumn 10, Issue 2, 2017, Pages 352-360

  Wildenberg, M E ^a   Koelink, P J ^a   Diederen, K ^a   Te Velde, A A ^a   Wolfkamp, S C S ^a   Nuij, V J ^b   Peppelenbosch, M P ^b   Nobis, M ^c   Sansom, O J ^c   Anderson, K I ^b   Van Der Woude, C J ^a   D'Haens, G R A M ^a   Van Den Brink, G R ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b ERASMUS MEDICAL CENTER   (Netherlands)

^c BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MERCAPTOPURINE; RAC1 PROTEIN; ATG16L1 PROTEIN, HUMAN; AUTOPHAGY RELATED PROTEIN; SMALL INTERFERING RNA;

ALLELE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATG16L1 GENE; AUTOPHAGY; CELL ADHESION; CELL CYCLE REGULATION; CELL MIGRATION; CELLULAR DISTRIBUTION; CONTROLLED STUDY; CROHN DISEASE; CYTOSKELETON; DENDRITIC CELL; DNA POLYMORPHISM; ENZYME ACTIVATION; ENZYME ACTIVITY; FEMALE; GENE; GENETIC RISK; HUMAN; HUMAN CELL; IMMUNOMODULATION; IMMUNOPATHOGENESIS; MOUSE; NONHUMAN; PHENOTYPE; PODOSOME; ANIMAL; C57BL MOUSE; CELL CULTURE; CELL MOTION; COLITIS, ULCERATIVE; GENETIC POLYMORPHISM; GENETIC PREDISPOSITION; GENETICS; IMMUNOLOGY; KNOCKOUT MOUSE; MEMBRANE STRUCTURE; METABOLISM; PATHOLOGY; PHYSIOLOGY; RISK;

6-MERCAPTOPURINE; ALLELES; ANIMALS; AUTOPHAGY; AUTOPHAGY-RELATED PROTEINS; CELL MEMBRANE STRUCTURES; CELL MOVEMENT; CELLS, CULTURED; COLITIS, ULCERATIVE; CROHN DISEASE; CYTOSKELETON; DENDRITIC CELLS; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; POLYMORPHISM, GENETIC; RAC1 GTP-BINDING PROTEIN; RISK; RNA, SMALL INTERFERING;

EID: 85014567275     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/mi.2016.65     Document Type: Article

References (37)

1. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohns disease. Nat. Genet. 40, 955-962 (2008).
2. Franke, A. et al. Genome-widemeta-Analysis increases to 71 the number of confirmed Crohns disease susceptibility loci. Nat. Genet. 42, 1118-1125 (2010).
3. McGovern, D.P. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332-337 (2010).
4. Lees, C.W., Barrett, J.C., Parkes, M. & Satsangi, J. New IBD genetics: common pathways with other diseases. Gut 60, 1739-1753 (2011).
5. Hampe, J. et al. A genome-wide association scan of nonsynonymous snps identifies a susceptibility variant for Crohn disease in atg16l1. Nat. Genet. 39, 207-211 (2007).
6. Cadwell, K. et al. A key role for autophagy and the autophagy gene atg16l1 in mouse and human intestinal paneth cells. Nature 456, 259-263 (2008).
7. Sadaghian Sadabad, M. et al. The atg16l1-T300a allele impairs clearance of pathosymbionts in the inflamed ileal mucosa of Crohns disease patients. Gut 64, 1546-1552 (2015).
8. Adolph, T.E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272-276 (2013).
9. Birmingham, C.L., Smith, A.C., Bakowski, M.A., Yoshimori, T.&Brumell, J.H. Autophagy controls salmonella infection in response to damage to the salmonella-containing vacuole. J. Biol. Chem. 281, 11374-11383 (2006).
10. Gutierrez, M.G. et al. Autophagy is a defense mechanism inhibiting bcg and mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753-766 (2004).
11. Schmid, D., Pypaert, M. & Munz, C. Antigen-loading compartments for major histocompatibility complex class ii molecules continuously receive input from autophagosomes. Immunity 26, 79-92 (2007).
12. Saitoh, T. et al. Loss of the autophagy protein atg16l1 enhances endotoxininduced il-1beta production. Nature 456, 264-268 (2008).
13. Wildenberg, M.E. et al. Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse. Gastroenterology 142, 1493-1503 (2012).
14. Poppe, D. et al. Azathioprine suppresses ezrin-radixin-moesin-dependent t cell-Apc conjugation through inhibition of vav guanosine exchange activity on rac proteins. J. Immunol. 176, 640-651 (2006).
15. Tiede, I. et al. Cd28-dependent rac1 activation is the molecular target of azathioprine in primary human cd4 t lymphocytes. J. Clin. Invest. 111, 1133-1145 (2003).
16. Hall, A. Rho gtpases and the actin cytoskeleton. Science 279, 509-514 (1998).
17. Ridley, A.J. et al. Cell migration: integrating signals from front to back. Science 302, 1704-1709 (2003).
18. Pagler, T.A. et al. Deletion of abca1 and abcg1 impairs macrophage migration because of increased rac1 signaling. Circ. Res. 108, 194-200 (2011).
19. Wheeler, A.P. et al. Rac1 and rac2 regulate macrophage morphology but are not essential for migration. J. Cell Sci. 119, 2749-2757 (2006).
20. Park, Y.M. et al. Oxidized ldl/cd36 interaction induces loss of cell polarity and inhibits macrophage locomotion. Mol. Biol. Cell 23, 3057-3068 (2012).
21. Colombel, J.F. et al. Infliximab, azathioprine, or combination therapy for Crohns disease. N. Engl. J. Med. 362, 1383-1395 (2010).
22. Thrasher, A.J. & Burns, S.O. Wasp: A key immunological multitasker. Nat. Rev. Immunol. 10, 182-192 (2010).
23. Nguyen, D.D. et al. Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice. Gastroenterology 143, 719-729 (2012).
24. Carroll, B. et al. The tbc/rabgap armus coordinates rac1 and rab7 functions during autophagy. Dev. Cell 25, 15-28 (2013).
25. Nethe, M. et al. Focal-Adhesion targeting links caveolin-1 to a rac1-degradation pathway. J. Cell Sci. 123, 1948-1958 (2010).
26. Kim, P.K., Hailey, D.W., Mullen, R.T. & Lippincott-Schwartz, J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc. Natl. Acad. Sci. USA 105, 20567-20574 (2008).
27. Pertz, O. Spatio-Temporal rho gtpase signaling-where are we now? J. Cell Sci. 123, 1841-1850 (2010).
28. Ravindran, R. et al. The amino acid sensor gcn2 controls gut inflammation by inhibiting inflammasome activation. Nature 531, 523-527 (2016).
29. DAlessio, S. et al. Vegf-c-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J. Clin. Invest. 124, 3863-3878 (2014).
30. du Pre, M.F. & Samsom, J.N. Adaptive t-cell responses regulating oral tolerance to protein antigen. Allergy 66, 478-490 (2011).
31. Spahn, T.W. et al. Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyers patches. Eur. J. Immunol. 32, 1109-1113 (2002).
32. Parikh, K. et al. Suppression of p21rac signaling and increased innate immunity mediate remission in Crohns disease. Sci.Transl. med. 6, 233ra253 (2014).
33. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889 (2006).
34. Johnsson, A.K. et al. The rac-fret mouse reveals tight spatiotemporal control of rac activity in primary cells and tissues. Cell Rep. 6, 1153-1164 (2014).
35. Nobis, M. et al. Intravital flim-fret imaging reveals dasatinib-induced spatial control of src in pancreatic cancer. Cancer Res. 73, 4674-4686 (2013).
36. Weersma, R.K. et al. Confirmation of multiple crohns disease susceptibility loci in a large dutch-belgian cohort. Am. J. Gastroenterol. 104, 630-638 (2009).
37. Wolfkamp, S.C. et al. Atg16l1 and nod2 polymorphisms enhance phagocytosis in monocytes of Crohns disease patients. World J. Gastroenterol. 20, 2664-2672 (2014).