The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility

Abstract

Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein that regulates Itch, an E3 ubiquitin ligase that ubiquitylates JunB, thereby preventing interleukin (IL)-4 and IL-5 production. Mice lacking Ndfip1 or Itch develop T helper type 2 (TH2)-mediated inflammation in the skin and lungs and die prematurely. In this study we show that Ndfip1 − / − mice also develop inflammation in the gastrointestinal tract. Inflammation is characterized by infiltration of eosinophils and T cells and is accompanied by a failure to gain weight. T cells are both necessary and sufficient for eosinophil recruitment and inflammation. This is because Ndfip1 − / − T cells become activated and produce IL-5. Itch mutant mice develop much less severe gastrointestinal inflammation, suggesting that Ndfip1 regulation of Itch cannot entirely account for this phenotype and that Ndfip1 has both Itch-dependent and Itch-independent roles. Ndfip1 may also regulate human disease. We found single-nucleotide polymorphisms in the Ndfip1 locus that associate with inflammatory bowel disease. Taken together, our data support a role for Ndfip1 in gastrointestinal inflammation in both mice and humans.

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

“…In Ndfip1-deficient animals, tissue destruction mediated by potent IL-4 producing Th2 cells has been shown to cause increased IL-6 at tissue sites, and this is thought to drive an increase in mucosal Th17 generation in vivo 34. However, it is also possible that this increase in Th17 cells may be due to a loss of Ndfip1 within the T cell lineage.…”

The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation

“…Mice that lack Ndfip1 naturally develop severe T H 2-mediated inflammation in the skin, gut and lungs, exhibit high levels of circulating IgE and die prematurely4647. To date, the contribution of mast cells to the pathology in these mice is unknown but studies focusing on T cells have identified that activated T H 2-polarized CD4 + T cells are a feature, possibly due to elevated production of IL-2, IL-4 and IL-5 (refs 46, 48), as well as an inability to exit the cell cycle to abort T-cell clonal expansion in response to self and exogenous antigens49.…”

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

“…Mice lacking NDFIP1 develop a fatal T cell-mediated inflammatory disease associated with T cell activation, regulatory T cell dysfunction, and Th2-mediated organ pathology (Altin et al, 2014; Beal et al, 2011; Layman et al, 2017a; Oliver et al, 2006). NDFIP1 likely plays similar roles in humans, because NDFIP1 polymorphisms and ITCH deficiency are associated with inflammatory and autoimmune diseases (Ferreira et al, 2011; Franke et al, 2010; Hu et al, 2011; International Multiple Sclerosis Genetics et al, 2011; Lohr et al, 2010; Ramon et al, 2011). …”