An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity

• Published in: Mucosal immunology Vol. 4; no. 3; pp. 354 - 364
• Main Authors: Eri, R D, Adams, R J, Tran, T V, Tong, H, Das, I, Roche, D K, Oancea, I, Png, C W, Jeffery, P L, Radford-Smith, G L, Cook, M C, Florin, T H, McGuckin, M A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2011; Nature Publishing Group
• Subjects: 631/250; 692/699/1503/1581/1392/1388; Adaptive Immunity; Adoptive Transfer; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Colitis - genetics; Colitis - immunology; Colitis - physiopathology; Cytokines - genetics; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Disease Models, Animal; Disease Progression; Endoplasmic Reticulum - physiology; Gastroenterology; Gene Expression Regulation - immunology; Homeodomain Proteins - genetics; Humans; Immunity, Innate; Immunology; Inflammation; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Mice; Mice, Knockout; Mice, Mutant Strains; Mucin-2 - genetics; Mucin-2 - immunology; Mucin-2 - metabolism; Mutation, Missense - genetics; Stress, Physiological - immunology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology; Thymic Stromal Lymphopoietin
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2010.74

We recently characterized Winnie mice carrying a missense mutation in Muc2 , leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie , there was a fourfold increase in activated dendritic cells (DCs; CD11c + major histocompatibility complex (MHC) class II hi ) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T H 17 signature genes Il17a , IL17f , Tgfb , and Ccr6 , particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple T H 1, T H 2, and T H 17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4 + T lymphocytes. Loss of T and B lymphocytes in Rag1 -/- × Winnie ( RaW ) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1 -/- , indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/T H 17 response, similar to that of human ulcerative colitis.