Abstract
Immature neutrophils and HLA-DRneg/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+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/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 (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.
Highlights
Despite advances in interventional therapies patients with large acute myocardial infarction (AMI) are at higher risk of heart failure morbidity and mortality.[1]
We explored whether increased frequency of immature neutrophils and HLA-DRneg/low monocytes are linked to circulating levels of immune regulators and acute inflammation markers such as G-CSF, S100A9/S100A8, MMP-9, NGAL, MPO, IL-6, TNF-α, IL-1ß and IFN-. Since a crucial role for immature neutrophils in the orchestration of adaptive immunity has recently emerged, we mostly focused on neutrophil-mediated regulation of T-cell response
We found that CD10neg neutrophils strongly enhanced IFN-γ and interleukin 12 (IL-12) production by CD4+ T-cells from CMV+ patients (Figure 9A, 9B), when co-cultured using a transwell system where CD4+ T-cells in the lower chamber were separated from neutrophils in the upper chamber
Summary
Despite advances in interventional therapies patients with large acute myocardial infarction (AMI) are at higher risk of heart failure morbidity and mortality.[1]. The role of immature neutrophils as well as HLA-DRneg/low monocytes in immune mechanisms operating during AMI remains largely unexplored. We explored whether increased frequency of immature neutrophils and HLA-DRneg/low monocytes are linked to circulating levels of immune regulators and acute inflammation markers such as G-CSF, S100A9/S100A8, MMP-9, NGAL, MPO, IL-6, TNF-α, IL-1ß and IFN-. Immature neutrophils and HLA-DRneg/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. Methods and Results: We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Conclusions: Immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI
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