Myeloid-Derived Suppressor Cells Modulate Aortic Aneurysm Formation Via Cxcr2 And Il-17 Signaling

Aortic aneurysm formation is associated with vascular inflammation and remodeling mediated via CD4+ T cell-secreted IL-17A production. Our hypothesis is that innate myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of myeloid precursor and progenitor cells, exhibit an immunoregulatory role in the progression of aortic inflammation during abdominal aortic aneurysm (AAA) formation. The trafficking and migration of MDSCs to the aortic tissue and role of CXCR2 and programmed death-1 (PD-1) receptor signaling was deciphered using an in vivo elastase-treatment model of AAA as well as in vitro co-culture experiments. We used an established murine AAA model of topical elastase-treatment in the present study. Preliminary data showed that elastase-treatment of C57BL/6 (wild-type; WT) mice resulted in significant increase in infrarenal aortic diameter causing AAA formation on day 14 that was significantly inhibited by a combined treatment with anti-CXCR2 and PD-1 antibodies. A multi-fold increase in MDSCs (CD11b+Gr-1+) in aortic tissue of elastase-treated WT mice on days 7 and 14 occurred compared to controls. Co-culture of MDSCs with aortic endothelial cells in the presence of anti-CXCR2 antibody inhibited the transmigration of MDSCs through the endothelial barrier. Moreover, transient elastase treatment of co-cultures of anti-CD3/CD28 treated mononuclear cells with MDSCs significantly enhanced IL-17A secretion compared to cultures without MDSCs. Our results indicate that MDSCs may play a contributory role in aortic inflammation by trafficking in a CXCR2-dependent manner and promotion of IL-17A secretion, signifying the importance of MDSC-mediated immunoregulation of aortic aneurysms.