Response to Letter Regarding Article, “Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice”
It is now clear that release of metalloproteinase–9 (MMP-9)2 inhibition by tissue inhibitor of MMP-1 (TIMP-1)1 is beneficial during the acute phase of CVB3 myocarditis, but chronic MMP activation is detrimental3 after infection has been cleared. We investigated the course of coxsackievirus B3 (CVB3)–induced viral myocarditis within a murine MMP-9 knockout model.2 On accumulating initial data, it was clear that a detailed study was required to support our observation that MMP-9 was protective during acute CVB3 infection and myocarditis. We noted that CVB3 infection within the pancreas and liver was also higher in the MMP-9 knockout mice, as compared with their wild-type counterparts. MMP-9 was clearly playing a role in the control and clearance of virus, system wide. These results are consistent with what has been reported about the role of MMP-9 in clearance of bacterial Staphylococcus aureus infection.4
Our study results can be reconciled with those of Heymans et al,3 in that the myocarditis at day 35 after infection investigated in the Heymans study is best suppressed with TIMP-1 administration and urokinase-type plasminogen activator inhibition. We and others1 reported on models at day 9 after CVB3 infection,2 which is well known to be within the window of acute CVB3 infection. Crocker et al1 have recently reported that TIMP-1 knockout mice experience reduced levels of cardiac inflammation and mortality, 8 days after infection. But one is well served to suppress a chronic immune response (that includes MMP-9 expression) at much later time points.3 Thus, the emerging scenario is that it may be best to preserve MMP expression during primary viral and bacterial infection to promote pathogen clearance,1,2 whereas it is best to control the host MMP-9 response at later time points to prevent immune-mediated destruction of tissue after infection, as Heymans et al have shown.3
TIMP-1 has more than 1 target, and surely more are yet to be discovered. As Pinto and Heymans previously discussed, we also find it difficult to conclude that an alteration in TIMP-1 or plasminogen urokinase can indicate a detrimental role for MMP-9 alone during chronic inflammation. An underlying pathogenesis could be related to cleavage of cytokines and chemokines, to mediate activation or inactivation, or cleavage of extracellular matrix to pave the way for immune cells, roles which have been attributed to MMP-9.5 On the other hand, over 24 vertebrate MMP genes are known, and, for this reason, other MMPs (known and yet to be discovered) may have an even more profound impact on the immune response.
Many important studies have focused on the effect of TIMP-1 and the MMPs, and these have provided great insight into the pathogenesis of inflammation disequilibrium. However, as we have shown,2 it is necessary to carefully dissect the constituents of the inflammatory response to determine the real culprits in complex pathogenesis. We therefore suggest that the recent studies of Heymans et al and ourselves constitute progress and not a paradox.
Cheung C, Marchant D, Walker EK, Luo Z, Zhang J, Yanagawa B, Rahmani M, Cox J, Overall C, Senior RM, Luo H, McManus BM. Ablation of matrix metalloproteinase-9 increases severity of viral myocarditis in mice. Circulation. 2008; 117: 1574–1582.
Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH, Padalko E, Neyts J, Schultheiss HP, Van de Werf F, Carmeliet P, Pinto YM. Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation. 2006; 114: 565–573.
Renckens R, Roelofs JJ, Florquin S, de Vos AF, Lijnen HR, van't Veer C, van der Poll T. Matrix metalloproteinase-9 deficiency impairs host defense against abdominal sepsis. J Immunol. 2006; 176: 3735–3741.