The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines (175.11)

Abstract

Abstract Ndfip1 is an adaptor that promotes polyubiquitylation by the E3 ubiquitin ligase Itch. Mice that lack either Ndfip1 or Itch develop a severe TH2-mediated inflammatory disease at sites of environmental antigen exposure, including the lung. Here we demonstrate that lungs from Ndfip1-/- mice showed increased numbers of neutrophils and TH17 cells. This was not because Ndfip1-/- T cells are intrinsically biased towards TH17 differentiation. In fact, fewer Ndfip1-/- T cells differentiated into TH17 cells in vitro due to the overproduction of IL-4 production. Rather, TH17 differentiation in vivo was increased in Ndfip1-/- mice due to elevated numbers of IL-6 producing eosinophils. Interestingly, mice lacking both Ndfip1 and IL-4 had levels of IL-6 comparable to WT controls and these Ndfip1-/- IL-4-/- mice had fewer TH17 cells in their lungs compared to Ndfip1-/- IL-4+/+ mice. These results indicate that TH2 inflammation, such as that observed in Ndfip1-/- mice, can increase TH17 differentiation by recruiting IL-6 producing eosinophils into secondary lymphoid organs and tissues. This may explain why TH17 cells develop within an ongoing TH2 inflammatory response, such as asthma.