Bacterial flagellin triggers myocardial innate immune responses and acute contractile failure

Background

Septic shock is associated with severe cardiac dysfunction, whose mechanisms remain partly undefined. Recent data suggested that it might be triggered by the direct action of microorganisms and their products on the heart itself. We previously showed that flagellin, the protein monomer from bacterial flagella, is a potent activator of NFκB-dependent proinflammatory signaling in cultured cardiomyocytes. In the present study, we investigated whether flagellin might induce such an inflammation in the heart in vivo and contribute to cardiac dysfunction.

Methods

Mice were injected intravenously with 1 μg flagellin. At selected timepoints (30 minutes to 4 hours), the effects of flagellin were evaluated by its ability to activate NFκB, mitogen-activated protein kinases and downstream signaling. Expression of the flagellin receptor TLR5 was also investigated. Cardiac function was evaluated after 4 hours using a microtip pressure–volume catheter inserted into the left ventricle. Also, human cardiac tissue was obtained from the right atrium in patients undergoing elective coronary artery bypass grafting surgery, to determine the presence of TLR5 in the human heart.

Results

Cultured cardiomyocytes, as well as hearts from mice and humans, expressed TLR5 protein at a high level. Flagellin activated NFκB and the mitogen-activated protein kinases p38 and JNK in cardiomyocytes in vitro and in vivo, and also upregulated the transcription of TNFα and MIP-2. In vivo, flagellin also induced the recruitment of neutrophils within the heart. Functionally, flagellin induced significant increases in end-systolic and end-diastolic left ventricle volumes, indicating cardiac dilation, and a significant reduction of end-systolic elastance and maximal elastance, indicating depressed myocardial contractility. In contrast, no change in the slope of the end-diastolic pressure–volume relationship was noted.

Conclusion

Bacterial flagellin induces a prototypical inflammatory response in cardiomyocytes in vitro and in the myocardium in vivo. These effects are associated with a profound alteration of the left ventricle systolic function in vivo, suggesting that flagellin may represent a critical mediator of cardiac dysfunction in septic shock.