Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

Abstract

COVID-19, caused by SARS-CoV-2 virus, emerged as a pandemic disease posing a severe threat to global health. To date, sporadic studies have demonstrated that innate immune mechanisms, specifically neutrophilia, NETosis, and neutrophil-associated cytokine responses, are involved in COVID-19 pathogenesis; however, our understanding of the exact nature of this aspect of host–pathogen interaction is limited. Here, we present a detailed dissection of the features and functional profiles of neutrophils, dendritic cells, and monocytes in COVID-19. We portray the crucial role of neutrophils as drivers of hyperinflammation associated with COVID-19 disease via the shift towards their immature forms, enhanced degranulation, cytokine production, and augmented interferon responses. We demonstrate the impaired functionality of COVID-19 dendritic cells and monocytes, particularly their low expression of maturation markers, increased PD-L1 levels, and their inability to upregulate phenotype upon stimulation. In summary, our work highlights important data that prompt further research, as therapeutic targeting of neutrophils and their associated products may hold the potential to reduce the severity of COVID-19.

SARS-CoV-2 infection: The role of PD-1/PD-L1 and CTLA-4 axis

“…Studies show the importance of cytotoxic CD8 + T-cells in controlling primary SARS-CoV-2 infections. In other words, the increase of cytokines such as IL-10, IL-6 and TNF-α in these patients and their role in reducing T-cells worsens the disease's condition [ 62 ]. New therapies for the cure of COVID-19 patients could be fundamental approaches such as targeting the pathways of immunosuppressive adjusting molecules like Tim-3, PD-1, increasing cellular immune functions by increasing T-cell and NK cell counts, and functions, not only in the treatment of cancer, but also, in the face of respiratory infections [ 38 , 63 ].…”

“…It has been suggested that, changes in the PD-1/PD-L1 pathway in chronic viral infections, like the human immunodeficiency virus (HIV), indicate the rearrangement of monocytes and dendritic cells (DCs) by signal transducer and activator of transcription 3 (STAT3)-dependent IL-10 production in response to the viral infection [ 42 , 43 ]. Moreover, elevated IL-10 levels in COVID-19 patients may also indicate the role of the PD-1/PD-L1 axis in the development of acute viral infections and monocyte rearrangement [ 44 ]. Neutrophils of the patients with COVID-19 are not able to regulate the expression of PD-L1 on the surface of immune cells compared to a healthy individual, so the levels of PD-L1's expression in these patients is low.…”

“…Neutrophils of the patients with COVID-19 are not able to regulate the expression of PD-L1 on the surface of immune cells compared to a healthy individual, so the levels of PD-L1's expression in these patients is low. Patients with more severe states had greater expressions of PD-L1 on both monocytes and DCs [ 44 ]. The examination of the individuals with severe clinical symptoms three weeks after the onset of signs, and elevated expressions of PD-1, perforin and granzyme B in CD4+ or CD8+ cells, showed that the role of T-cells in the progression of the patients' clinical condition is significant [ 45 ].…”

“…Monocytes involved in COVID-19, similar to the monocytes involved in hepatitis C infection, have been reported to over expressions of PD-L1 and IL-10, and down expressions of Human Leukocyte Antigen – DR isotype (HLA-DR) and CD86 [ 61 ]. In addition, it has been observed that in the COVID-19 disease, unlike monocytes and DCs, neutrophils express less PD-L1; In contrast, they are characterized by the significant secretion of proinflammatory cytokines induced by ss-RNAs [ 62 ]. Correspondingly, neutrophils are more abundant in the peripheral blood during the course of COVID-19, given their weaker ability to secrete cytokines than monocytes and DCs [ 62 ] ( Fig.…”

“…In addition, it has been observed that in the COVID-19 disease, unlike monocytes and DCs, neutrophils express less PD-L1; In contrast, they are characterized by the significant secretion of proinflammatory cytokines induced by ss-RNAs [ 62 ]. Correspondingly, neutrophils are more abundant in the peripheral blood during the course of COVID-19, given their weaker ability to secrete cytokines than monocytes and DCs [ 62 ] ( Fig. 1 ).…”