Nature Communications (Feb 2019)

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,
  • Yatrik M. Shah

DOI
https://doi.org/10.1038/s41467-019-08581-8
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 16

Abstract

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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.