Abstract

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.

Details

Title
Intestinal non-canonical NFκB signaling shapes the local and systemic immune response
Author
Ramakrishnan, Sadeesh K 1 ; Zhang Huabing 2 ; Ma Xiaoya 2 ; Jung Inkyung 2 ; Schwartz, Andrew J 2 ; Triner, Daniel 2 ; Devenport, Samantha N 2 ; Das, Nupur K 2 ; Xue Xiang 2   VIAFID ORCID Logo  ; Zeng, Melody Y 3 ; Hu Yinling 4 ; Mortensen, Richard M 2 ; Greenson, Joel K 5 ; Cascalho Marilia 6 ; Wobus, Christiane E 7 ; Colacino, Justin A 8   VIAFID ORCID Logo  ; Nunez, Gabriel 9 ; Liangyou, Rui 10   VIAFID ORCID Logo  ; Shah, Yatrik M 10 

1  University of Pittsburgh, Department of Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
2  University of Michigan, Department of Molecular & Integrative Physiology, Michigan, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
3  University of Michigan, Department of Pathology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Internal Medicine, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
4  National Institutes of Health, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
5  University of Michigan, Department of Pathology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
6  University of Michigan, Transplantation Biology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Surgery, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Microbiology and Immunology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
7  University of Michigan, Department of Microbiology and Immunology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
8  University of Michigan, Department of Environmental Health Sciences, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Department of Nutritional Sciences, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
9  University of Michigan, Department of Pathology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Comprehensive Cancer Center, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
10  University of Michigan, Department of Molecular & Integrative Physiology, Michigan, USA (GRID:grid.214458.e) (ISNI:0000000086837370); University of Michigan, Internal Medicine, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-08581-8
ProQuest document ID
2177676581
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.