12R-HETE acts as an endogenous ligand of Nur77 in intestine and regulates ILC3s plasticity

Group 3 innate lymphoid cells (ILC3s), a heterogeneous population, are tissue-resident myeloid cells and have an essential role in bacterial infection. Although the plasticity of NKp46- CCR6- double-negative (DN) ILC3s toward the NKp46+ ILC3s is an important process in the development of intestinal immunity, the underlying molecular mechanisms responsible for this process remain poorly understood. Nur77 is an orphan receptor which regulates intestinal ILC3s expansion. However, the impact of Nur77 on the plasticity of intestinal ILC3s remains unclear. Here, we generated Nur77 null mice and investigated ILC3s expansion. The deficiency of Nur77 inhibited the mouse small intestinal ILC3s expansion and conversion of NKp46- ILC3s to NKp46+ ILC3s. We identified that 12R-HETE derived from arachidonic acid (ARA) in mouse intestine is an endogenous ligand of Nur77 and activates its transcriptional activity. The treatment with 12R-HETE promoted the differentiation of NKp46- ILC3s into NKp46+ ILC3s by enhancing the T-bet expression, thereby increased IFN-{gamma} production from NKp46+ ILC3s, and reduced the susceptibility to bacterial infection in WT, but not Nur77-/-, suckling mice. An integrated analysis of ATAC-seq and Smart RNA-seq showed that Rflnb, Impdh1, Map1s, and Gtpbp3 might be downstream targeted genes of Nur77 in response to 12R-HETE and mediate the regulation of ILC3s plasticity. In the presence of mycophenolic acid, an inhibitor of IMPDH, 12R-HETE no longer regulated the percentages of ROR{gamma}t+ILC3s and NKp46+ILC3s. We conclude that 12R-HETE acts as an endogenous ligand of Nur77, and regulates the ILC3s expansion and plasticity, and in turn, gut homeostasis and pathogen defense.