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A15048 Monocytic Interleukin-27 Suppresses CD8+IFN-&ggr;+ T cells and Cardiac Injury

Objectives: The balance between inflammation and its resolution regulates tissue injury and repair. Herein, we investigate the molecular events involved in the resolution of inflammation during hypertensive cardiac injury. Methods: RNA-seq and RT-PCR were performed and revealed that interleukin (IL)-27, an anti-inflammatory cytokine, was significantly elevated in response to Ang II infusion. Flow cytometry, and bone marrow (BM) transplantation studies (reciprocal WT to Ebi3−/− mice, Ebi3 is a subunit of IL-27) showed that IL-27 was primarily expressed in BM-derived CD11b+F4/80+ macrophages. Results: Cardiac inflammation and fibrosis were exacerbated in Ebi3−/− and wild-type mice reconstituted with Ebi3−/− BM compared with WT BM. Mechanistically, expression of monocytic chemokines was increased in Ebi3−/− hearts, which resulted in the recruitment of more F4/80+Ly6Chigh cells into circulation and Ly6C+CCR2+ heart-infiltrating macrophages. Furthermore, infiltration of both CD4+ and CD8+ T cells was increased in Ebi3−/− hearts, while the depletion of CD8+, but not CD4+ T cells could rescue the aggravated macrophage infiltration, inflammation and fibrosis in Ebi3−/− mice by suppressing the expression of interferon (IFN)-&ggr;. Conclusion: Our findings demonstrate that macrophage-derived IL-27 exerts its inflammation-resolving effects by suppressing CD8+ T cell production of IFN-&ggr;, leading to protection from cardiac inflammation and injury.