Invasion of inflammatory cells into the injured heart during viral myocarditis needs to be restricted to a level that supports viral elimination and at the same time prevents detrimental processes such as cardiomyocyte dysfunction and cardiac remodeling. The ubiquitin-proteasome-system (UPS) is vital for cells to preserve the intracellular balance of protein synthesis and destruction. By degrading short-lived poly-ubiquitin-tagged proteins it determines the availability of regulatory proteins and controls different signaling events. Increased proteolytic activity of the UPS upon formation of immunoproteasomes (IP) to preserve cellular viability and to counterbalance detrimental outcomes of inflammation during CoxsackievirusB3 (CVB3)-myocarditis. This study investigated down-stream pathways that are affected by IP-dependent protein degradation to protect the heart from inflammatory damage. The soluble pattern recognition factor long pentraxin 3 (PTX3) was found to be up-regulated in CVB3-myocarditis. PTX3 as part of the innate humoral immune response is known to modulate inflammation by facilitating the clearance of apoptotic cells and simultaneously counterbalancing the invasion of leucocytes into inflamed hearts. PTX3-induction critically relied on intact IP-function. The lack of PTX3-induction as observed in cardiac homogenates from CVB3-infected IP-deficient mice coincided with severe inflammatory cardiac damage. Supporting our in vivo results, further in vitro studies confirmed that cardiomyocytes and macrophages contribute to PTX3 secretion as detected by quantitative real-time PCR, immunoblot analysis and ELISA. Primary cardiomyocytes and bone-marrow derived macrophages up-regulate PTX3 in an IP-dependent manner. Specific inhibition of IP activity by small molecular compounds down-regulated PTX3 levels in TNF-α stimulated cardiomyocytes. Further studies aim to unravel the impact of IP function in the timely control of regulatory proteins that are involved in the regulation of PTX3 transcription. Preliminary data point towards impaired IκBα degradation in IP-deficient cardiomyocytes, thereby limiting NFκB-dependent signaling processes and PTX3 expression. In conclusion, this study reports on the role of timely protein processing by the proteasome system to modulate inflammatory injury in a mouse model of viral myocarditis. IP function is critical for PTX3-induction. Given the disease attenuating potential of PTX3 also in acute myocardial ischemia this study has a high impact for cardiac inflammation in general.