Epstein–Barr Virus‐Induced 3 attributes to TLR7‐mediated splenomegaly

Masanori Iseki, Yuma Sakamoto, Daiki Takezaki, Yoshihiro Matsuda, Mariko Inoue, Shin Morizane, Tomoyuki Mukai

Epstein–Barr virus‐induced 3 (EBI3) functions as a component of the heterodimer cytokine IL‐27, which regulates innate and acquired immune responses. The expression of EBI3 gene is induced by Toll‐like receptors (TLRs). Repeated treatment with imiquimod (IMQ), a TLR7 agonist, induces splenomegaly and cytopaenia due to increased splenic function. Although immune cell activation is speculated to play a role in chronic infection‐mediated splenomegaly, the detailed mechanisms remain unknown. This study shows that IMQ treatment induces marked splenomegaly and severe bicytopaenia (anaemia and thrombocytopaenia) in wild‐type mice. In IMQ‐treated mice, myeloid cell populations in the spleen increased, and extramedullary haematopoiesis was observed. RNA‐seq analysis revealed the upregulation of type I interferon (IFN)‐related genes in the spleens of IMQ‐treated mice. IMQ‐induced pathological changes were partially mitigated by EBI3 deficiency. To investigate the mechanism of the improved phenotypes in the Ebi3 KO mice, we examined the involvement of IL‐27, a heterodimer of EBI3 and IL‐27p28. The expression of Il27a, which encodes IL‐27p28, was increased in the spleen and peripheral blood by IMQ treatment. Furthermore, IL‐27 stimulation upregulated type I IFN‐related genes in bone marrow‐derived macrophage cultures without type I IFN. These findings suggest that EBI3 deficiency mitigated IMQ‐mediated pathological changes, presumably via a lack of IL‐27 formation. Our study thus provides insights into the molecular mechanisms underlying chronic infection‐mediated splenomegaly.

Immunology

Wiley

175

1

36

51

10.1111/imm.13905

https://doi.org/10.1111/imm.13905