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

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

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08581-8

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