Ribosomal Oxygenase 2 Constrains A Latent Anthelmintic Pathway In Intestinal Epithelial Cells

Expulsion of parasitic gastrointestinal nematodes requires diverse effector mechanisms coordinated by a Th2-type response. The evolutionarily conserved JmjC protein ribosomal oxygenase 2 (Riox2, formerly Mina) has been shown to repress IL4, a key Th2 cytokine, suggesting Riox2 may negatively regulate parasite expulsion. Here we report that expulsion of parasitic nematodes was indeed accelerated in Riox2 deficient mice. Unexpectedly, this was associated not with an elevated Th2 but rather an impaired Th1-type response. Further, in vitro T cell differentiation, reciprocal bone marrow chimera and conditional KO experiments demonstrated that retarded parasite expulsion and a normal Th1-type response both required Riox2 in intestinal epithelial cells (IECs). Gene profiling experiments in IECs revealed anti-microbial α-defensin peptides to be the major target of Riox2-dependent repression. In vitro exposure to recombinant α-defensin peptides caused cytotoxic damage to whipworms. These results identify a latent IEC-intrinsic anthelmintic pathway actively constrained by Riox2 and point to α-defensins as important effectors that together with Riox2 would be attractive therapeutic targets for the control of nematode infection. RNA-Seq analysis of enriched cecal epithelial cells of uninfected Villin-Cre+::Riox2(flox/flox) and Villin-Cre+::Riox2(+/+) littermates; and from ceca of Riox2(-/-) and Riox2(+/+) littermates 21 days following Trichuris muris (TM) infection.