Inflammation that follows a heart attack is known to promote healing, but if left unchecked, can lead to irreparable heart damage and failure. New findings reveal the immune cells and key signaling compounds that play a role in regulating the inflammation following an attack. These involve macrophages and the production of inflammatory signaling molecules, known as specialized proresolving mediators (SPMs). The recently published study in Science Signaling comes from collaborators in the University of Alabama at Birmingham and Brigham and Women's Hospital at Boston.The team used a mouse model in which myocardial infarction in the heart was induced by surgical coronary ligation. The goal was to define the inflammatory and resolving responses, by quantifying leukocyte populations and concentrations of SPMs within the heart and spleen following the heart attack.Among the team’s findings was the observation that the spleen was not only a reservoir for leukocytes, but also a source of SPMs before the infarction. However, one day after the heart attack, leukocytes were found depleted in the spleen and were instead elevated in the infarcted left ventricle. Higher levels of SPMs were also found in the heart, particularly comprising resolvins, maresin, lipoxins, and protectin. Genes expressing lipoxygenases, which produce SPMs were also found upregulated. Moreover, the increase in SPMs was found to be temporally correlated with the resolution of inflammation.To investigate the relevant immune cells, the spleen and left ventricle were treated with clodronate, which selectively kills macrophages. This resulted in reduced expression of lipoxygenases and generation of SPMs, suggesting that macrophages were necessary for producing SPMs.
Altogether, the team’s findings suggest that in the event of a heart attack, leukocytes--particularly macrophages--are mobilized from the spleen to the heart to produce proresolving mediators. Thus, the idea of preventing immune cell infiltration after a heart attack may also delay healing and recovery by letting inflammation to continue. The team proposes further investigation of macrophage-derived SPMs in heart failure.
Image: Model showing that leukocytes in the spleen generated SPMs through lipoxygenase isoforms that advance the resolution of inflammation and healing in the left ventricle after myocardial infarction. Image courtesy of Ganesh Halade and AAAS Science Signaling.