Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses

Abstract

Adiponectin (APN) is an immunomodulatory adipocytokine that improves outcome in patients with virus-negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Here, we investigated whether APN modulates cardiac inflammation and injury in coxsackievirus B3 (CVB3) myocarditis. Myocarditis was induced by CVB3 infection of APN-KO and WT mice. APN reconstitution was performed by adenoviral gene transfer. Expression analyses were performed by qRT-PCR and immunoblot. Cardiac histology was analyzed by H&E-stain and immunohistochemistry. APN-KO mice exhibited diminished subacute myocarditis with reduced viral load, attenuated inflammatory infiltrates determined by NKp46, F4/80 and CD3/CD4/CD8 expression and reduced IFNβ, IFNγ, TNFα, IL-1β and IL-12 levels. Moreover, myocardial injury assessed by necrotic lesions and troponin I release was attenuated resulting in preserved left ventricular function. Those changes were reversed by APN reconstitution. APN had no influence on adhesion, uptake or replication of CVB3 in cardiac myocytes. In acute CVB3 myocarditis, cardiac viral load did not differ between APN-KO and WT mice. However, APN-KO mice displayed an enhanced acute immune response, i.e. increased expression of myocardial CD14, IFNβ, IFNγ, IL-12, and TNFα resulting in increased cardiac infiltration with pro-inflammatory M1 macrophages and activated NK cells. Up-regulation of cardiac CD14 expression, type I and II IFNs and inflammatory cell accumulation in APN-KO mice was inhibited by APN reconstitution. Our observations indicate that APN promotes CVB3 myocarditis by suppression of toll-like receptor-dependent innate immune responses, polarization of anti-inflammatory M2 macrophages and reduction of number and activation of NK cells resulting in attenuated acute anti-viral immune responses.

Myocarditis

“…206,207 But in a recent study, administration of adiponectin in CVB3-induced acute myocarditis mouse models promoted the development of myocarditis by suppression of TLR-dependent innate immune responses. 208 Several other immune modulators have been tested in experimental animal models or cell cultures and exhibited inspiring therapeutic potentials. Nonsteroidal anti-inflammatory drugs are considered effective anti-inflammatory therapeutics and have been applied in the treatment of pericarditis.…”

Adiponectin attenuates profibrotic extracellular matrix remodeling following cardiac injury by up-regulating matrix metalloproteinase 9 expression in mice

“…The CVB3 positive strand copy number was measured for all CVB3‐infected animals using triplicates of left ventricular cDNA samples (Jenke et al. ).…”

“…Adequate anesthesia was tested by monitoring withdrawal response to foot pinch. For induction of experimental CVB3 myocarditis 6-8 weeks old male mice were infected by intraperitoneal injection of 200 lL phosphate-buffered saline (PBS) containing 5 9 10 5 plaque forming units (PFU) of transfection-derived purified CVB3 (Nancy strain; ATCC Number: VR-30) (Jenke et al 2014). Seven days p.i.…”

“…A minimum CVB3 positive strand copy number of 1 9 10 3 per ng cDNA in left ventricular tissue specimens as determined by qRT-PCR was used as threshold for inclusion of infected animals into the study. The CVB3 positive strand copy number was measured for all CVB3-infected animals using triplicates of left ventricular cDNA samples (Jenke et al 2014).…”

Epigenetic Modulation in Periodontitis: Interaction of Adiponectin and JMJD3-IRF4 Axis in Macrophages

“…The results indicated that JMJD3 was down-regulated in obesity. Adiponectin (APN), a factor secreted by adipose tissue which is down-regulated in obesity, functions to switch macrophage polarization from M1 to M2 (Jenke et al, 2014), thereby attenuating chronic inflammation. Intriguingly, our results indicated that APN contributed to JMJD3 up-regulation, reduced macrophage infiltration in obese adipose tissue, and abolished the up-regulation of JMJD3 in peritoneal macrophages isolated from DIO mice when challenged with Porphyromonas gingivalis LPS (pg.lps).…”