Journal Article

Intestinal non-canonical NFκB signaling shapes the local and systemic immune response

Jung, Inkyung, Greenson, Joel K, Triner, Daniel, Mortensen, Richard M., Cascalho, Marilia, Ramakrishnan, Sadeesh K., Schwartz, Andrew J., Ma, Xiaoya, Hu, Yinling, Shah, Yatrik M., Rui, Liangyou, Wobus, Christiane E., Colacino, Justin A., Das, Nupur K., Zeng, Melody Y., Zhang, Huabing, Devenport, Samantha N., Nunez, Gabriel, Xue, Xiang

2019

Overview

Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The function of M-cells in systemic inflammatory responses are still unclear. Here we show that epithelial non-canonical NFkB signaling mediated by NFkB-inducing kinase (NIK) is highly active in intestinal lymphoid follicles, and is required for M-cell maintenance. Intestinal NIK signaling modulates M-cell differentiation and elicits both local and systemic IL-17A and IgA production. Importantly, intestinal NIK signaling is active in mouse models of colitis and patients with inflammatory bowel diseases; meanwhile, constitutive NIK signaling increases the susceptibility to inflammatory injury by inducing ectopic M-cell differentiation and a chronic increase of IL-17A. Our work thus defines an important function of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis. Microfold cells (M-cell) are specialized cells of the intestine that sample luminal microbiota and dietary antigens. Here the authors show that epithelial non-canonical NFκB signalling, as induced by NIK, is important for M-cells maintenance, yet constitutive NIK activation is associated with gut inflammation and inflammatory bowel disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 14/34 / 14/63 / 38 / 38/61 / 38/77 / 59 / 631/250/127/1213 / 631/250/21/1293 / 631/250/347 / 631/250/516/1909 / 64 / 64/60 / 82/29 / Animal models / Animals / Antigens / B-Lymphocytes - metabolism / Blotting, Western / Bone marrow / Cell differentiation / Cells / Colitis / Colitis - immunology / Colitis - metabolism / Colon / Colon - metabolism / Colon - pathology / Diarrhea / Differentiation (biology) / Enzyme-Linked Immunosorbent Assay / Feces / Flow Cytometry / Follicles / Glycoproteins / Homeostasis / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunoglobulin A / Immunoglobulin A - metabolism / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Interleukin-17 - metabolism / Intestine / Intestines - immunology / Kinases / Maintenance / Mice / Microbiota / Microorganisms / multidisciplinary / NF-kappa B - metabolism / NF-κB protein / Protein Serine-Threonine Kinases / RNA, Ribosomal, 16S - genetics / Rodents / Science / Science (multidisciplinary) / Sepsis / Sepsis - genetics / Sepsis - metabolism / Signal Transduction - physiology / Signaling / Small intestine / Tumor necrosis factor-TNF