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Review
. 2022 Apr 13;11(8):1322.
doi: 10.3390/cells11081322.

Neutrophil Functional Heterogeneity and Implications for Viral Infections and Treatments

Affiliations
Review

Neutrophil Functional Heterogeneity and Implications for Viral Infections and Treatments

Lily Chan et al. Cells. .

Abstract

Evidence suggests that neutrophils exert specialized effector functions during infection and inflammation, and that these cells can affect the duration, severity, and outcome of the infection. These functions are related to variations in phenotypes that have implications in immunoregulation during viral infections. Although the complexity of the heterogeneity of neutrophils is still in the process of being uncovered, evidence indicates that they display phenotypes and functions that can assist in viral clearance or augment and amplify the immunopathology of viruses. Therefore, deciphering and understanding neutrophil subsets and their polarization in viral infections is of importance. In this review, the different phenotypes of neutrophils and the roles they play in viral infections are discussed. We also examine the possible ways to target neutrophil subsets during viral infections as potential anti-viral treatments.

Keywords: heterogeneity; neutrophil; plasticity; subsets; viral infection.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Morphologically distinct subsets of neutrophils are observed in circulation. Isolation of neutrophils from the blood by density gradient centrifugation will give two band layers of leukocytes. The lower band would have the polymorphonuclear cells and is where neutrophils are typically purified from. However, there are neutrophils found in the higher band that have lower density. Blood from healthy individuals was examined for these populations of neutrophils, commonly denoted as low density neutrophils (LDNs) and normal density neutrophils (NDNs). Differences in phenotypic surface markers were observed, as well as differences in their ability to produce reactive oxygen species and phagocytic capacities. Therefore, from blood-derived mononuclear cells, two different subsets can be detected and isolated based on density. Furthermore, these two subsets are functionally different and can be distinguished by flow cytometric assessment of surface markers [92].
Figure 2
Figure 2
Neutrophils can be fine-tuned and influenced by their micro-environment to exert detrimental or protective immunological functions during anti-viral responses. Examples include recruitment of leukocytes through chemokine release and presentation of viral antigens to T cells. Additionally, neutrophils support type I interferon responses that mediate anti-viral immunity. However, neutrophils can also function in a manner that is harmful to the host. For example, neutrophils produce an array of pro-inflammatory cytokines, which when uncontrolled can lead to tissue damage. Similarly, when NETosis becomes dysregulated, there can be substantial bystander damage to tissues. Additionally, neutrophils have immunosuppressive capabilities that can hinder anti-viral responses, thereby reducing viral clearance.
Figure 3
Figure 3
Neutrophils are heterogeneous, with each subset exerting specific immunomodulatory functions during viral infections such as those caused by hepatitis C virus (HCV). (A) Granulocyte myeloid-derived suppressor cell polarization occurs through activation of the extracellular signal-regulated protein kinase (ERK)-1/2 mitogen-activated protein kinase (MAPK) pathway, with further augmentation by IL-10-dependent signal transducer and activator of transcription (STAT)-3 phosphorylation. Eventually, the proliferation of autologous T cells and production of IFN-γ are repressed, leading to persistence of HCV [111]. (B) Human neutrophils can also function as antigen-presenting cells. Neutrophils pulsed with the cognate antigens pp65 from cytomegalovirus (CMV) or influenza hemagglutinin were able to present the antigens to autologous antigen-specific CD4+ T cells via major histocompatibility complex (MHC) class II and induce proliferation of helper T cells at a low but consistent rate both in vitro and ex vivo [139].

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