Expansion of CD10^neg neutrophils and CD14⁺HLA-DR^neg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction.

Abstract

Immature neutrophils and HLA-DR^neg/low 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 CD16⁺CD66b⁺CD10^neg neutrophils and CD14⁺HLA-DR^neg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10^neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10^neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4⁺CD28^null T-cells. Notably, the expansion of circulating CD4⁺CD28^null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10^neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10^neg 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^neg/low 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 (CD11b^posLy6G^posCD101^neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10^neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.