Protein modification with ISG15 (ISGylation) represents a major type I IFN–induced antimicrobial system. Common mechanisms of action and species-specific aspects of ISGylation, however, are still ill defined and controversial. We used a multiphasic coxsackievirus B3 (CV) infection model with a first wave resulting in hepatic injury of the liver, followed by a second wave culminating in cardiac damage. This study shows that ISGylation sets nonhematopoietic cells into a resistant state, being indispensable for CV control, which is accomplished by synergistic activity of ISG15 on antiviral IFIT1/3 proteins. Concurrent with altered energy demands, ISG15 also adapts liver metabolism during infection. Shotgun proteomics, in combination with metabolic network modeling, revealed that ISG15 increases the oxidative capacity and promotes gluconeogenesis in liver cells. Cells lacking the activity of the ISG15-specific protease USP18 exhibit increased resistance to clinically relevant CV strains, therefore suggesting that stabilizing ISGylation by inhibiting USP18 could be exploited for CV-associated human pathologies.

Cardiomyocyte death as a result of viral infection is an excellent model for dissecting the inflammatory stress response that occurs in heart tissue. We reported earlier that a specific proteasome isoform, the immunoproteasome, prevents exacerbation of coxsackievirus B3 (CVB3)-induced myocardial destruction and preserves cell vitality in heart tissue inflammation. Following the aim to decipher molecular targets of immunoproteasome-dependent proteolysis, we investigated the function and regulation of the soluble PRR Pentraxin3 (PTX3). We show that the ablation of PTX3 in mice aggravated CVB3-triggered inflammatory injury of heart tissue, without having any significant effect on viral titers. Thus, there might be a role of PTX3 in preventing damageassociated molecular pattern-induced cell death. We found that the catalytic activity of the immunoproteasome subunit LMP7 regulates the timely availability of factors controlling PTX3 production. We report on immunoproteasome-dependent alteration of ERK1/2 and p38MAPKs, which were both found to be involved in PTX3 expression control. Our finding of a cardioprotective function of immunoproteasome-dependent PTX3 expression revealed a crucial mechanism of the stress-induced damage response in myocardial inflammation. In addition to antigen presentation and cytokine production, proteolysis by the immunoproteasome can also regulate the innate immune response during viral infection.Keywords: Infection r Inflammation r Innate immunity r Myocarditis r Pentraxin3 r Proteasome r Stress response r Virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe myocardium can be injured by various pathophysiological processes. Myocarditis is an excellent model of heart muscle Correspondence: Dr. Antje Voigt e-mail: antje.voigt@charite.de injury for dissecting processes of the heart stress response to inflammation. In developed countries, myocarditis most commonly results from a virus infection, often by coxsackievirus B3 (CVB3) and adenoviruses. Fulminant injury of the heart muscle in * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 620Anna Paeschke et al. Eur. J. Immunol. 2016. 46: 619-633 viral myocarditis is attributed to both, direct virus-mediated cytotoxic effects and destruction of the heart muscle by the immune system [1,2]. The balance of intrinsic and innate immune mechanisms determines whether there is repair of the heart muscle or progression to chronic inflammation. This process involves the engagement of pattern recognition receptors (PRRs) either with pathogen-associated molecular patterns (PAMPs) such as viral RNA, or, upon the release of endogenous material, with damageassociated molecular patterns (DAMPs) [3]. Our knowledge on disease course in patients comes mainly from the mouse model of CVB3 myocarditis. Cardiotropic CVB3 infects mice and replicates to high titers, causing acute myocarditis (ACM) that faithfully mirrors...

This review aims to summarize the current knowledge in which measures this intraabdominal fat participates in the regulation of intestinal inflammation with a particular focus on differences and possible parallels in Crohn's disease and diverticulitis. The available data allow for suggesting that each inflamed diverticula mechanistically reflects Crohn's disease on a miniature scale.