Dendritic Cells Derived MMP9 Fuels Sepsis-Induced Cardiac Dysfunction Through JNK/AP1 Driven Pro-Inflammatory Cytokine and Nitric Oxide Storm

Metalloproteinase9 is an important inflammatory mediator, but its contribution to sepsis-induced myocardial dysfunction (SIMD) remains unclear. In this study, we found that MMP9 deletion in mice evoked resistance to LPS-triggered septic cardiac dysfunction and lethality, accompanied by heavily reduced serum level of inflammatory factors and the myocardial damage markers. Similar results were acquired when an MMP9 inhibitor was used to treat LPS-induced sepsis, indicating that MMP9 promoted the progression of SIMD. It is well-known that DCs can induce inflammatory response to promote septic tissue damage. Notably, MMP9-/- BMDCs were significantly more effective in reducing sepsis-induced myocardial dysfunction compared to WT BMDCs. Mechanistically, MMP9 deficiency in BMDCs mainly curtailed the release of IL-6, IL-1β, IL-17 A, and nitric oxide via the JNK/AP1 pathway, thus safeguarding cardiomyocytes from death. Collectively, this study contributed new insights into the role of MMP9 in DCs within the context of SIMD.