Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is responsible for over 11 million fatalities worldwide annually [1,2]. The majority of patients with sepsis exhibit abnormal cardiac function, commonly termed sepsis-induced cardiomyopathy (SICM) which is characterized by a reduced LVEF and is associated with high mortality [3]. Septic hearts are associated with massive cell death and catastrophic inflammatory storm. Of note, cardiac dysfunction is reversible if septic patients survive later, suggesting there were endogenous defensive system driving body to return to homeostasis [[3], [4], [5]]. However, the mechanisms facilitating cardiac rehabilitation in SICM have not been fully elucidated.

The inflammation plays vital roles in regulating tissue homeostasis in SICM [4]. Co-ordination of the inflammation response relies on host and pathogen derived resolved pathways [4,6]. It is now appreciated that endogenous lipid mediators are produced that coordinate the host response to promote resolution of inflammation [7,8]. These novel lipid mediators, coined specialized pro-resolving mediators (SPMs), are derived from polyunsaturated fatty acids including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) [[7], [8], [9]]. However, the metabolic changes of cardiac SPMs during SICM remains unknown.

Resolvin D2 (RvD2), a subgroup of the D-series Resolvins, has been reported to ameliorate muscle regeneration [10], brain ischemia reperfusion [11], atherosclerosis [12], acute lung injury [13] and cardiac remodeling post myocardial infarction [14] through reduce cell death and the resulting inflammatory and immune response [[10], [11], [12], [13], [14], [15], [16], [17], [18]]. However, whether RvD2 abnormalities mediate cardiac dysfunction and rehabilitation during SICM and the mechanism within deserves further elucidation.

Pyroptosis, a lytic form of cell death, is mediated by the formation of Gasdermin D (GSDMD) pores and releases alarmins (IL-1β) to induce the immune and inflammatory response during cardiac injury [[19], [20], [21], [22]]. Caspase-11, an intracellular LPS receptor and a key component of the innate immune response to Gram-negative bacterial infection, cleaves GSDMD into pore-forming peptides to induce pyroptosis [23,24]. Caspase-11 activation by cytosolic LPS contributes to the formation of blood coagulation [25,26] and acute lung injury [27] during sepsis; hence, these observations led us to postulate that Caspase-11 signaling might mediate SICM. RvD2 reduce cell death through inhibiting autophagy and apoptosis to promoting resolution of inflammation in no-sepsis induced inflammatory disease [[15], [16], [17], [18]]. However, whether RvD2 inhibits Caspase-11 signaling-mediated pyroptosis during SICM remains unclear.

In the present study, by Lipid mediator metabololipidomics and Liquid chromatography tandem mass spectrometry-based mediator profiling, we profiled the metabolic changes of cardiac SPMs, especially the D-series Resolvins, in the murine septic heart. We identified RvD2 that was critical for supporting the cardiac function under sepsis challenge. In addition, we found that RvD2 ameliorated cardiac injury of SICM through inhibiting GSDMD-mediated pyroptosis in endotoxemia and bacterial sepsis mice. Moreover, Caspase-11 activation in cardiomyocytes is responsible for GSDMD-mediated pyroptosis during SICM, while RvD2 inhibits Caspase-11 signaling to alleviate SICM. Finally, plasma RvD2 levels are indicators of SICM from healthy controls or sepsis patients by a multicenter case-control study. These results extend our understanding of the mechanisms that drive cardiac dysfunction in sepsis and point to RvD2/Caspase-11/GSDMD signaling pathway as potential targets to prevent SICM.