Abstract
Severe cases of coronavirus disease 2019 (COVID-19), caused by infection with SARS-CoV-2, are characterized by a hyperinflammatory immune response that leads to numerous complications. Production of proinflammatory neutrophil extracellular traps (NETs) has been suggested to be a key factor in inducing a hyperinflammatory signaling cascade, allegedly causing both pulmonary tissue damage and peripheral inflammation. Accordingly, therapeutic blockage of neutrophil activation and NETosis, the cell death pathway accompanying NET formation, could limit respiratory damage and death from severe COVID-19. Here, we demonstrate that synthetic glycopolymers that activate signaling of the neutrophil checkpoint receptor Siglec-9 suppress NETosis induced by agonists of viral toll-like receptors (TLRs) and plasma from patients with severe COVID-19. Thus, Siglec-9 agonism is a promising therapeutic strategy to curb neutrophilic hyperinflammation in COVID-19.
Highlights
Runaway inflammation in coronavirus disease 2019 (COVID19) is thought to lead to numerous complications, including potentially fatal pneumonia and acute respiratory distress syndrome (ARDS).[1−3] While the specific causal factors of inflammation in COVID-19-related ARDS are unknown and likely multifarious, an emerging hypothesis posits that hyperactivation of neutrophils initiates and drives this response (Figure 1).[4−12] Neutrophils are immune cells of the myeloid lineage that are involved in numerous innate immune functions
Extracellular DNA and tissue damage from neutrophil extracellular traps (NETs)-associated enzymes act as proinflammatory signals to other immune cells[15−17] and are proposed to initiate the hyperinflammatory cascade in COVID-19, leading to ARDS and potentially death. Consistent with this hypothesis, NETs have been extensively observed both at the site of infection[18−21] and in the periphery.[19,21]. Both SARS-CoV-2 virions and serum/plasma from COVID19 patients have been shown to induce NETosis of neutrophils isolated from healthy donors in vitro, consistent with the local and peripheral inflammatory responses observed in COVID19.19,21,22 the specific signals that induce NETosis in viral disease remain an open question; viral ligands for toll-like receptors (TLRs), host damage-associated molecular patterns, antiviral cytokines (e.g., IL-8 and IFNγ), and activated platelets have all been implicated, but which if any of these is sufficient to induce NETosis is still debated.[21,23]
NETosis has been linked to numerous inflammatory pathologies, including thrombosis and sepsis, both of which are observed in patients with COVID-19.4 During NETosis, inflammatory stimuli signal neutrophils to import calcium ions, which activate protein arginine deiminase 4 (PADI4).[24,25]
Summary
Runaway inflammation in coronavirus disease 2019 (COVID19) is thought to lead to numerous complications, including potentially fatal pneumonia and acute respiratory distress syndrome (ARDS).[1−3] While the specific causal factors of inflammation in COVID-19-related ARDS are unknown and likely multifarious, an emerging hypothesis posits that hyperactivation of neutrophils initiates and drives this response (Figure 1).[4−12] Neutrophils are immune cells of the myeloid lineage that are involved in numerous innate immune functions. We observed results similar to previously published data sets using neutrophils stimulated with either R84848 or PMA.[49] several phosphosites were found to be differentially regulated in both data sets, including those involved in neutrophil degranulation and calcium flux, consistent with the described mechanism of NETotic cell death.[24,49] These results indicate that the TLR-7/8 agonist R848 induces NETosis in primary neutrophils This compound can be used to model local inflammation associated with viral infection, including in COVID-19. Previous work by von Gunten, Varki, and their respective co-workers has shown that engagement of Siglec-9 leads to apoptotic and nonapoptotic death pathways as well as immunosuppression in neutrophils.[26,50] we hypothesized that Siglec-9-mediated immunosuppression and cell death could override the NETotic effect of antiviral TLR signaling To test this notion, we used our previously described Siglec-9 agonist, pS9L40 as well as the two control glycopolypeptides pLac and pS9L-sol (Figures 2 and S4). No unexpected or unusually high safety hazards were encountered
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