Abstract 228: Inflammasome-Primed Neutrophils Return to the Bone Marrow to Stimulate Leukocytosis Following Myocardial Infarction

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened number of neutrophils in the circulation. However, the mechanism that sustain their number and recruitment to the infarcted heart are unclear. Here, we show that in a mouse model of MI (permanent ligation of LAD), neutrophils are rapidly recruited to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins acting either in an autocrine or paracrine manner, primed the Nod Like Receptor (NLR) family Pyrin Domain Containing 3 (Nlrp3) inflammasome in naïve neutrophils via their interaction with the Toll Like Receptor (TLR) 4. The interaction did not result in the release of IL1β systemically. However, the primed neutrophils, loaded with pro-interleukin-1β (IL-1β) returned to the bone marrow (BM) in a CXCR4 (C-X-C-motif chemokine receptor 4)- dependent manner. While at the BM, the primed-neutrophils released IL-1β through Gasdermin D pores and, stimulated granulopoiesis in a cell-autonomous manner. Strategies aimed at preventing the Nlrp3 inflammasome-priming or re-entry of the primed neutrophils to the BM dampened MI-induced granulopoiesis and markedly improved cardiac function. In subjects with acute ST-elevation myocardial infarction (STEMI), the number of neutrophils in the circulation increased both at the time of admission and following revascularization. Most importantly, patients with higher peak neutrophil counts demonstrated significantly higher incidence of major adverse cardiovascular events (MACE) during the one year follow up period. Similar to mouse data, the plasma levels of IL-1β did not change in STEMI patients at any time. However, the circulating neutrophils carried greater amounts of pro-IL-1β confirming our mouse data that granulopoiesis is likely not induced by systemic but locally delivered IL-1β by reverse migrating neutrophils. These data reveal a new paradigm of how circulatory cells establish direct communication between organs by delivering signaling molecules directly at the sites of action rather through systemically.