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

Nat Commun. 2019 Feb 8;10(1):660. doi: 10.1038/s41467-019-08581-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Blotting, Western
  • Colitis / immunology
  • Colitis / metabolism
  • Colon / metabolism
  • Colon / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunoglobulin A / metabolism
  • Interleukin-17 / metabolism
  • Intestines / immunology
  • Mice
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases
  • RNA, Ribosomal, 16S / genetics
  • Sepsis / genetics
  • Sepsis / metabolism
  • Signal Transduction / physiology

Substances

  • Immunoglobulin A
  • Interleukin-17
  • NF-kappa B
  • RNA, Ribosomal, 16S
  • Protein-Serine-Threonine Kinases