The Role of GM-CSF in Myocardial Infarction
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CitationChoi, Jennifer. 2019. The Role of GM-CSF in Myocardial Infarction. Doctoral dissertation, Harvard Medical School.
AbstractMyocardial infarction (MI) is characterized by an obstruction of blood flow to the myocardium, leading to deprivation of oxygen and eventually, irreversible tissue death. After tissue death, intense inflammation occurs, which is characterized by the recruitment of leukocytes to the infarcted heart tissue by chemokines, cytokines, and the complement system. In addition to the immune system’s essential role in healing the infarcted tissue, it also contributes to a deleterious process called ‘ventricular remodeling,’ characterized by negative alterations in cardiac geometry, function, and structure, which can lead to heart failure in the long term. One poorly understood component of the inflammatory response in MI is granulocyte-macrophage colony-stimulating factor (GM-CSF), a growth factor implicated in emergency hematopoiesis in the setting of injury or infection. We hypothesized that GM-CSF plays a critical role in amplifying inflammation after MI, leading to worse outcomes.
In a preliminary survival study using a mouse model of permanent left anterior descending artery (LAD) ligation, the Swirski lab found that GM-CSF knockout (Csf2 KO) mice had significantly higher survival rates than wild type mice as well as decreased leukocyte recruitment into the infarct and improved cardiac function at 21 days post MI in spite of similar infarct size on day 1. Here, we go on to show that GM-CSF expression was shortly and transiently upregulated in infarcted heart tissue after MI, as evidenced by increased GM-CSF mRNA and protein levels. The infarcted tissue was the main source of GM-CSF and within the infarcted tissue, GM-CSF was primarily produced by fibroblasts, but not leukocytes, endothelial cells, or other stromal cells. The primary trigger for GM-CSF expression was found to be DNA, an important danger-associated molecular pattern (DAMP) released after MI that binds to TLR9 and signals through Myd88. Lastly, we found that Ly6Chigh monocytes and macrophages in the infarcted tissue responded to GM-CSF by producing CCL2, an important chemokine for monocyte and macrophage chemotaxis. These results support the hypothesis that GM- CSF is a critical cytokine in the inflammatory response after MI and potential target for therapeutic intervention.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42063325