Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals.
A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3-Dectin-1-FcγRIIB receptor complex that activated β-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.
Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Meimei
M
Shan
Maurizio
M
Gentile
John R
JR
Yeiser
A Cooper
AC
Walland
Victor U
VU
Bornstein
Kang
K
Chen
Bing
B
He
Linda
L
Cassis
Anna
A
Bigas
Montserrat
M
Cols
Laura
L
Comerma
Bihui
B
Huang
J Magarian
JM
Blander
Huabao
H
Xiong
Lloyd
L
Mayer
Cecilia
C
Berin
Leonard H
LH
Augenlicht
Anna
A
Velcich
Andrea
A
Cerutti
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009055:Mouth / Q000276:immunology*; D055262:Mucin-2 / Q000235:genetics / Q000502:physiology; D009093:Mucus / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism; D000099181:Dectin-1
D037502:Galectin 3; D037181:Lectins, C-Type; D055262:Mucin-2; D016328:NF-kappa B; D017452:Receptors, IgG; D051176:beta Catenin; D000099181:Dectin-1