title: The epithelia-specific membrane trafficking factor AP-1B controls gut immune homeostasis in mice.
abstract: OBJECTIVE
  Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis.
  
  
  METHODS
  The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice.
  
  
  RESULTS
  Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease.
  
  
  CONCLUSIONS
  AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.
authors.affiliation: Department of Supramolecular Biology, Graduate School of Nanobioscience, Yokohama City University, Yokohama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kimura
authors.forename: Fubito
authors.initials: F
authors.lastname: Nakatsu
authors.forename: Masumi
authors.initials: M
authors.lastname: Ohmae
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Mandai
authors.forename: Toru
authors.initials: T
authors.lastname: Sato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Date
authors.forename: Masashi
authors.initials: M
authors.lastname: Ebisawa
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Kato
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Obata
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Yuki I
authors.initials: YI
authors.lastname: Kawamura
authors.forename: Taeko
authors.initials: T
authors.lastname: Dohi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Katsuno
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D033961:Adaptor Protein Complex 1 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D033966:Adaptor Protein Complex beta Subunits / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D033983:Adaptor Protein Complex mu Subunits / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism* / Q000502:physiology; D002463:Cell Membrane Permeability; D003092:Colitis / Q000276:immunology* / Q000382:microbiology; D003106:Colon; D003424:Crohn Disease / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009113:Muramidase / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology* / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023084:alpha-Defensins / Q000378:metabolism; D023083:beta-Defensins / Q000378:metabolism
chemical_list: C499064:AP1M2 protein, human; D000209:Acute-Phase Proteins; D033961:Adaptor Protein Complex 1; D033966:Adaptor Protein Complex beta Subunits; D033983:Adaptor Protein Complex mu Subunits; C403682:Ang3 protein, mouse; D023181:Antimicrobial Cationic Peptides; C510064:Ap1b1 protein, mouse; D054804:Cathelicidins; D007070:Immunoglobulin A; D020381:Interleukin-17; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011506:Proteins; D018121:Receptors, Cytokine; C088549:RegIII protein, mouse; D009418:S100 Proteins; D014409:Tumor Necrosis Factor-alpha; D023084:alpha-Defensins; D023083:beta-Defensins; C071332:Lcn2 protein, mouse; D012260:Ribonucleases; C046366:angiogenin; C519253:Ang4 protein, mouse; D012259:Ribonuclease, Pancreatic; D009113:Muramidase