Despite advances in interventional therapies patients with large acute myocardial infarction (AMI) are at higher risk of heart failure morbidity and mortality (Heusch and Gersh, 2017). Immunity and inflammation play a key role in the pathogenesis of ischemic heart failure, and the complex role of immune cells during the wound healing process after injury is currently the focus of intensive research efforts. Understanding the immune mechanisms operating during AMI could pave the way to develop more effective strategies to prevent progressive dilative cardiac remodeling, functional deterioration and heart failure and to reduce adverse cardiovascular events.

HLA-DR^neg/low monocytes and immature neutrophils expand in pathological conditions such as cancer, infection, and inflammation, (Gabrilovich and Nagaraj, 2009) and have recently been implicated in the pathogenesis of severe COVID-19 (Silvin et al., 2020; Deutsche COVID-19 OMICS Initiative (DeCOI) et al., 2020). A rapid depression of monocytic HLA-DR expression was observed in patients with AMI (Haeusler et al., 2012). Maréchal et al., 2020 studying neutrophil phenotypes in acute coronary syndrome found increased percentage of immature low density neutrophils in patients with ST-elevation MI. However, the role of immature neutrophils as well as HLA-DR^neg/low monocytes in immune mechanisms operating during AMI remains largely unexplored.

By integrating flow cytometric immunophenotyping of monocyte, neutrophil, and lymphocyte subsets, ex vivo experiments with sorted cells as well as bioinformatic tools this study investigated the appearance and the functional immune properties of immature neutrophils and HLA-DR^neg/low monocytes in patients with AMI. Moreover, we explored whether increased frequency of immature neutrophils and HLA-DR^neg/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-γ.

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. Environmental factors especially cytomegalovirus (CMV) infection are likely to provide a significant contribution to functional diversity of T-cells. Therefore, we also investigated the impact of CMV on CD4⁺ T-cell homeostasis and on the immunoregulatory properties of immature neutrophils derived from patients with AMI.

In addition, using a mouse model of reperfused AMI we addressed whether immature neutrophils migrate into the injured myocardium and populate heart-draining lymph nodes in response to acute ischemic injury.

Innate immune mechanisms play a paramount role during AMI and the functional heterogeneity of monocytes and neutrophils have been the focus of intensive research in recent years. This study highlights for the first time that immature CD16⁺CD66b⁺CD10^neg neutrophils and CD14⁺HLA-DR^neg/low monocytes promoting proinflammatory immune responses expand in the peripheral blood from patients with large AMI. We also show that immature neutrophils are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion, using a mouse model of AMI. Furthermore, we found a potential link among increased frequency of immature CD10neg neutrophils and elevated IFN-γ levels, especially in cytomegalovirus-seropositive patients with expanded CD4⁺CD28^null T-cells. Finally, we could show that CD10^neg neutrophils enhance CD4⁺ T-cells IFN-γ production by a contact-independent mechanism involving IL-12 (Figure 10).

Figure 10

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This study uncovered that CD10 can be used as a surface marker to identify the immature neutrophil population that expands and promotes proinflammatory effects in patients suffering from AMI. We believe that immature CD10^neg neutrophils derive from MI-induced emergency granulopoiesis. Both mature (segmented) and immature banded neutrophils are released from the bone marrow presumably to meet the high demand for more neutrophils, especially in patients with large AMI. Not surprisingly, in our study higher frequency of circulating CD10^neg neutrophils was associated with increased systemic concentrations of G-CSF, an essential regulator of neutrophil trafficking from the bone marrow to the blood and important neutrophil survival factor (Costa et al., 2019; Silvestre-Roig et al., 2020). Recently, CD10 has been proposed as a marker that distinguishes mature from immature neutrophils in healthy volunteers receiving G-CSF for stem cell mobilization (Marini et al., 2017).

Multiple clinical trials have evaluated the use of G-CSF in patients with AMI after successful revascularization. The majority of these studies found that effective stem cell mobilization with G-CSF therapy failed to improve left ventricular recovery (Traverse, 2019). Our findings suggest that the therapeutic benefits of G‐CSF therapy after AMI might be compromised due to the release of immature proinflammatory CD10^neg neutrophils.

However, neutrophils may be released from the bone marrow in response to increased damage-associated molecular patterns such as S100A8/S100A9, secreted from neutrophils as mediators of sterile inflammation (Sreejit et al., 2020). Of interest, we found that circulating CD10^neg neutrophils express high amounts of S100A9, indicating that immature neutrophils could be an important source of this alarmin in patients with AMI.

Under inflammatory conditions neutrophils traffic to inflamed tissues as well as to draining lymph nodes (Costa et al., 2019; Leliefeld et al., 2015) modulating T cell-mediated immune responses. Our data from the mouse model of AMI are first to provide evidence that immature neutrophils can populate heart-draining lymph nodes in response to acute ischemic injury. It is intriguing to speculate that CD10^neg neutrophils migrate into lymph nodes where they could encounter T-cells and shape adaptive immune responses.

Emerging evidence indicates that immature neutrophils can be T-cell suppressive or do possess T-cell stimulatory capacities, displaying disease‐specific functional plasticity (Costa et al., 2019; Rahman et al., 2019). Immunostimulatory immature CD10^neg neutrophils appear in the circulation of G-CSF–treated healthy volunteers and contact-dependent mechanisms account for their immunoregulatory functions (Marini et al., 2017). Here, we provide mechanistic evidence that immature CD10^neg neutrophils from patients with AMI, in a contact-independent way involving IL-12, enhance priming for IFN-γ production in activated CD4⁺ T-cells. Thus, through diverse mechanisms immature CD10^neg neutrophils may exert immunostimulatory/proinflammatory functions actively participating in the regulation of adaptive immunity.

Genetic and environmental factors shape the immune system over time. Several studies have demonstrated that persistent CMV infection is associated with changes in T-cell phenotype and function (Nikolich-Zugich, 2008; Wertheimer et al., 2014; Davenport et al., 2020). Our results highlight that CD4⁺CD28⁺ T-cells from CMV-seropositive AMI patients are skewed toward a Th1 phenotype, producing large amounts of IFN-γ in presence of CD10^neg neutrophils. However, results obtained in vitro cannot be translated directly to the in vivo situation and several cellular and molecular mechanisms could have led to increased circulating levels of the pleiotropic cytokine IFN-γ after AMI. Notably, using bioinformatic tools (PCA and hierarchical clustering) we were able to highlight the tight relationship among the peripheral expansion of immature CD10^neg neutrophils, CMV-altered CD4⁺ T-cell homeostasis and high levels of IFN-γ in patients with large AMI. Thus, determination of circulating CD10^neg neutrophils levels, particularly in the context of persistent CMV infection, might help to identify patients at risk for excessive inflammatory immune response.

Although a pathogenetic role of CD4⁺CD28^null T-cells in coronary artery disease and atherogenesis have been recognized, important issues have remained unresolved (Dumitriu et al., 2009). A recent study revealed complex associations between of CD4⁺CD28^null T-cells and cardiovascular disease (Tomas et al., 2020). CD4⁺CD28^null T-cells are associated with a lower risk for first-time coronary events in a population-based cohort. In contrast, in patients with advanced atherosclerotic disease an increased frequency of CD4⁺CD28^null T-cells was associated with more frequent major adverse cardiovascular events (Tomas et al., 2020). Our findings point to a potential link between CMV induced immune alterations following repeated antigen exposure and the peripheral expansion of CD4⁺CD28^null T-cells in ACS patients. CMV has been associated with atherosclerosis and increased risk for cardiovascular diseases. Recent clinical data showed that myocardial ischemia in CMV-seropositive patients leads to significant changes in the composition of the CD8⁺ T-cell repertoire, accelerating immunosenescence (Hoffmann et al., 2015).

In spite of numerous studies on polymorphonuclear myeloid cells the presence and functional characteristics of immature neutrophils is underexplored in the setting of AMI in mice. The present study demonstrated for the first time that CD101 can be used as a marker to define the maturation status of neutrophils mobilized into the peripheral blood in response to ischemia and recruited to sites of ischemic injury after reperfusion. Previous studies in a human model of experimental endotoxemia showed that banded neutrophils exhibit efficient migration to sites of infection (van Grinsven et al., 2019). Moreover, developmental analysis of bone marrow neutrophils revealed that immature neutrophils possess functional migratory machinery and are recruited to the periphery of tumor-bearing mice (Evrard et al., 2018). Of note, we found that immature CD101^neg neutrophils are released into the bloodstream within minutes after reperfusion and are capable of efficient migration to ischemic tissues, displaying increased expression of MMP-9 and IL-1ß at 3 and 24 hr after reperfusion, respectively. There are significant differences between mouse and human immunology. In mice, 10–25% of circulating leukocytes are neutrophils, while in humans neutrophils are the predominant leukocyte population, accounting for 50–70% of leukocytes. Moreover, the transit time of leukocytes may be quite different (Mestas and Hughes, 2004; Mackey et al., 2019; Riehle and Bauersachs, 2019). During homeostasis, trafficking of neutrophils/myeloid cells from bone marrow into the circulation takes between 1–2 days in mice and 5–8 days in humans (Mackey et al., 2019). Such differences should be considered when comparing animal and human studies on immune mechanisms underlying wound healing. However, future studies that employ intravital microscopy are required to track the fate of immature neutrophils mobilized from the bone marrow and recruited to the ischemic myocardium as well as lymph nodes after AMI.

The recruitment of immune cells to sites of tissue repair is a complex highly regulated process involving cytokines, chemokines, and interactions between infiltrating immune cells. HLA-DR^neg/low monocytes from patients with AMI are not immunosuppressive but express high amounts of IL1R1. Thus, immature neutrophils, as an important source of IL-1ß in the reperfused heart, may be actively involved in the recruitment of HLA-DR^neg/low cells. Saxena et al., 2013 showed that IL1R1 signaling mediates early recruitment of Ly6C^hi monocytes to the infarcted myocardium. Reperfused myocardial infarction had intense infiltration with Ly6C^hi monocytes expressing IL1R1 that peaked after 24 hr of reperfusion (Saxena et al., 2013). Noteworthy, recent studies demonstrated that the failing human heart also contains HLA-DR^neg/low monocytes (Bajpai et al., 2018).

Several immune mechanisms operate during cardiac wound healing and IFN-γ plays different roles depending on the cellular and microenvironmental context intrinsically linked to the stages of ischemic injury. By integrating cell sorting and in vitro experiments, we found that macrophages differentiated from HLA-DR^neg/low monocytes produced more TNF-α, IL-6, and IL-1ß upon IFN-γ stimulation as HLA-DR^high monocyte-derived macrophages. These findings may support a role for HLA-DR^neg/low monocytes in pathogenic mechanisms operating during AMI and may, at least in part, explain why an expansion of circulating HLA-DR^neg/low monocytes correlates with circulating levels of TNF-α, IL-6, and IL-1ß.

The interleukin-1 pathway plays a key role in post-MI inflammation and the progression to heart failure (Abbate et al., 2020). Our in vitro mechanistic experiments with immune cells from AMI patients as well as mouse studies provide a potential linkage between the induction of immature CD10^neg neutrophils/HLA-DR^neg/low monocytes and increased interleukin-1 activity during AMI. Emerging evidences highlight that targeting interleukin-1 may hold promise for patients after MI (Buckley and Abbate, 2018). In STEMI patients, the interleukin-1 receptor antagonist anakinra significantly reduced the systemic inflammatory response. Moreover, in the CANTOS trial, administration of canakinumab (a monoclonal antibody targeting IL-1β) prevented the recurrence of ischemic events, reduced heart failure-related hospitalizations and mortality in patients with prior AMI (Buckley and Abbate, 2018).

Neutrophils may orchestrate post-MI healing through induction of MerTK expression and increased efferocytosis capacity of macrophages (Horckmans et al., 2017). Of interest, we found significantly higher expression of MerTK on macrophages differentiated from CD14⁺HLA-DR^neg/low monocytes and polarized in the presence of secretome derived from CD10^pos neutrophils. It is tempting to speculate that HLA-DR^neg/low monocytes had the potential to differentiate into macrophages with enhanced capacity to phagocyte apoptotic cells when exposed to CD10^pos neutrophils after AMI. Nevertheless, in vitro studies have limited ability to explain the complexity of macrophage activation within the infarct environment.

The apoptosis rate of CD10^neg neutrophils was strongly reduced compared with CD10^pos neutrophils. This finding is consistent with recent studies showing that cellular immaturity influences apoptosis (Marini et al., 2017; Wang et al., 2020). We also observed that CD101^neg neutrophils sorted from reperfused ischemic hearts were resistant to apoptosis. Apoptosis is essential for neutrophil functional shutdown, phagocytic clearance by macrophages and timely resolution of inflammation (Koedel et al., 2009; Elliott et al., 2017). Therefore, apoptosis resistance of immature neutrophils may play a crucial role, hitherto overlooked, after MI. Further depletion/modulation studies in mice will shed light on the immunoregulatory functions of immature neutrophils in the inflammatory response during wound healing.

In conclusion, this study shows that immature CD10^neg neutrophils and CD14⁺HLA-DR^neg/low monocytes expand in patients with AMI and highlights their potential role as triggers of immune/inflammatory dysregulation after ischemic injury. These findings could have major implications for understanding immunoregulatory mechanisms operating during AMI and for the development of future therapeutic strategies. Nevertheless, further studies deciphering the relationship between elevated CD14⁺HLA-DR^neg/low monocytes/CD10^neg neutrophils and ensuing mortality and morbidity after ischemic injury are necessary and ongoing.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1-figure supplement 1 and Figure 3-figure supplement 1.

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Author details

1. Daniela Fraccarollo

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration

   For correspondence

   fraccarollo.daniela@mh-hannover.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7756-6032

2. Jonas Neuser

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Resources, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Julian Möller

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1818-6782

4. Christian Riehle

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Resources, Writing - review and editing

   Competing interests

   No competing interests declared

5. Paolo Galuppo

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

6. Johann Bauersachs

   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

   Contribution

   Resources, Supervision, Funding acquisition, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

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