Abstract 14285: Adiponectin Promotes Development Of Coxsackievirus B3 Myocarditis By Suppressing The Acute Antiviral Immune Response
Background: Adiponectin (APN) is an immunomodulatory adipocytokine that modulates outcome in patients with virus negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Moreover, APN controls antigen specific T cell responses and viral replication in hepatitis. Here, we investigated whether APN modulates cardiac inflammation and injury in CVB3 myocarditis.
Methods: Myocarditis was induced by CVB3 infection of APN-KO and WT mice. Viral load was determined by plaque assay and in situ hybridization. Gene expression was measured by qRT-PCR and flow cytometry. Tissue histology was analyzed using H&E stained heart sections.
Results: On day 7 p.i. APN-KO mice developed less severe subacute myocarditis with reduced viral load, diminished formation of inflammatory infiltrates and attenuated expression of immune cell markers NKp46, F4/80, CD3, CD4, CD8 and CD45 as well as immune response mediators IFNß, IFNγ, TNFα, IL-1ß, IL-6, and IL-12. Moreover, the extent of necrotic lesions was less severe in hearts of APN-KO mice. In cultured cardiac myocytes APN had no influence on adhesion, uptake or replication of CVB3. Accordingly, in acute phase CVB3 myocarditis on day 3 p.i. cardiac viral load was unchanged in APN-KO mice. However, APN-KO mice displayed an intensified acute immune response designated by increased formation of inflammatory infiltrates in the myocardium and enhanced cardiac expression levels of macrophage and NK cell activation markers F4/80 and CD69 as well as immune response mediators IFNß, IFNγ, IL-12, TNFα and CCL2. At the same time, expression of the M2 macrophage polarization marker Mgl1 was reduced. Furthermore, APN-KO mice showed a higher number of IFNγ secreting NK cells that are important for virus clearance. Accordingly, APN inhibited TLR ligand induced IFNγ production in cultured NK cells.
Conclusion: Our observations indicate that APN promotes development of CVB3 myocarditis by modulating polarization of activated macrophages towards an anti-inflammatory M2 phenotype and influencing number and differentiation of NK cells resulting in a suppressed acute anti-viral immune response. Thus, in contrast to other models of inflammatory heart disease APN causes increased myocardial damage following CVB3 infection.
- © 2012 by American Heart Association, Inc.