The Expression profile of spleen and peripheral blood in imiquimod-treated Ebi3 gene deficient mice. Mus musculus

Epstein-Barr virus induced 3 (EBI3) is a gene activated by toll-like receptors (TLRs) stimulation and functions as a component of a heterodimer cytokine IL-27. IL-27 regulates both innate and acquired immune responses. Splenomegaly, an enlargement of the spleen, is known to be induced by chronic infectious diseases such as EB virus infection. Repeated treatment of imiquimod (IMQ; a TLR7 agonist) has been reported to induce splenomegaly and cytopenia due to increased splenic function. While immune cell activation is speculated to play a role in the pathogenesis of chronic infection-mediated splenomegaly, the detailed molecular mechanisms remain unknown. In this study, we demonstrated that IMQ treatment induced marked splenomegaly and severe bicytopenia (anemia and thrombocytopenia) in wild-type mice. Myeloid cell populations were increased in the enlarged spleen, and extramedullary hematopoiesis was observed in the IMQ-treated mice. RNA-seq analysis revealed upregulation of type I interferon (IFN)-related genes in the spleen of the IMQ-treated mice. EBI3 deficiency partially mitigated these IMQ-induced pathological changes. Additionally, we found that Il27 along with 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 cultures in the absence of type I IFN. In summary, our study indicate that EBI3 contributes to TLR7-induced splenomegaly and bicytopenia, likely via IL-27, providing insight into the molecular mechanisms underlying chronic infection-mediated splenomegaly.