Epstein-Barr virus induced 3 attributes to TLR7-mediated splenomegaly and bicytopenia

Epstein-Barr virus induced 3 (EBI3) is a gene induced by stimulation of toll-like receptors (TLRs) and functions as a component of a heterodimer cytokine IL-27. IL-27 regulates both innate and acquired immune responses; however, their function in vivo is still largely unknown. Splenomegaly, an enlargement of the spleen, is known to be induced by chronic infectious diseases, including infectious mononucleosis due to EB virus infection. Repeated treatment of imiquimod (IMQ; a TLR7 agonist) has been reported to induce splenomegaly and cytopenia due to increased splenic function. Although immune cell activation is speculated to be involved in the pathogenesis of chronic infection-mediated splenomegaly, the detailed molecular mechanism is unknown. Here, we demonstrated that IMQ induced marked splenomegaly and severe bicytopenia (anemia and thrombocytopenia) in the wild-type mice. Myeloid cells, not lymphoid cells, were increased in the enlarged spleen. Extramedullary hematopoiesis was observed in the enlarged spleen of the IMQ-treated mice. RNA-seq analysis revealed that type I interferon (IFN)-related genes were upregulated in the spleen and peripheral blood in IMQ-treated mice. Ebi3 deficiency partially retrieved these IMQ-induced pathological changes. We found that Il27 as well as Ebi3 genes were elevated by IMQ in the spleen and peripheral blood. Further, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage culture in the absence of type I IFN. Collectively, EBI3 contributes to TLR7-induced splenomegaly and bicytopenia, presumably via IL-27.