Myeloid-Specific Deletion of Lipid Plpp3 (Phosphate Phosphatase 3) Increases Cardiac Inflammation After Myocardial Infarction

Acute myocardial infarction (MI) leads to the activation of a systemic inflammatory response which is imperative for tissue healing, but uncontrolled/prolonged inflammation is detrimental to cardiac functional recovery.1 Lysophosphatidic acid (LPA), regulates monocytosis and promotes inflammation in the setting of MI as we have recently reported.2 LPA can be inactivated by lipid phosphate phosphatases (LPPs) and one of these enzymes, LPP3 plays a protective role in vascular injury and tissue healing.3, 4 However, the role of myeloid LPPs in cardiac inflammation post-MI is poorly understood.We generated a mouse model with myeloid-specific Plpp3 (gene encoding for LPP3) deletion (LysM-Plpp3 Δ ). 4 Myeloid cells in this model lack the expression of LPP3 even when stimulated in vitro.4 There were no significant differences in cardiac function or inflammation at baseline (BSL, unoperated 6-week-old mice) (Fig. 1A, B, and C).LysM-Plpp3 fl/fl and LysM-Plpp3 Δ underwent MI (permanent LAD ligation) or sham surgery.Myeloid deletion of LPP3 was associated with a higher mean number of cardiac Ly6C hi monocytes (CD45 + /Ly6G/C + /CD115 + , p<0.01) and pro-inflammatory macrophages (CD45 + /F4-80 + /CD86 + cells, p<0.001 and CD45 + /F4-80 + /CD11b + cells, p<0.001) compared to LysM-Plpp3 fl/fl littermate controls (Fig. 1A).Increased monocytosis and bone marrow hematopoietic myeloid progenitor cell proliferation have been closely linked to intense atherogenesis 5 and other inflammatory conditions.Flow cytometry analyses of BM cells isolated before and after MI revealed a significantly higher mean number of hematopoietic stem/progenitor cells (HSPCs), granulocyte-myeloid progenitors (GMPs), and common myeloid progenitors (CMPs) in LysM-Plpp3 Δ , corresponding with the higher mean number of infiltrating myeloid cells in the myocardium (Fig. 1B).Together, these results demonstrate that myeloid-specific LPP3 deletion results in increased myeloid progenitor cell proliferation and an aggravated inflammatory response after MI.