Expansion of CD10 neutrophils and CD14HLA-DR monocytes driving proinflammatory responses in patients with acute myocardial infarction.

Immature neutrophils and HLA-DR monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16CD66bCD10 neutrophils and CD14HLA-DR monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10 neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10 neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4CD28 T-cells. Notably, the expansion of circulating CD4CD28 T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10 neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10 neutrophils enhanced IFN-γ production by CD4 T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DR monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bLy6GCD101 cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10 neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.