2. Role of Neutrophils in COVID-19
Neutrophils are the immune system’s first responders having crucial
functions in immunity and repair. Upon activation, they produce
pro-inflammatory cytokines (including IL-6, TNF-α and IL-1β), generate
reactive oxygen species (ROS), release hematopoietic serine proteases
(neutrophil elastase, proteinase 3, and cathepsin G), microparticles and
neutrophil extracellular traps (NETs). Neutrophils possess
anti-microbial properties capable of not only killing both Gram-positive
and Gram-negative bacteria, but they can also act as a double edged
sword mediating tissue injury and perpetuating the inflammatory
response.(Kolaczkowska and Kubes 2013) NETs, ROS and serine proteases
can all independently, or collectively, upregulate thromboinflammatory
processes.
In the context of COVID-19, neutrophilia signifies worse outcomes, with
autopsy studies showing neutrophil infiltration in pulmonary
capillaries, acute capillaries with fibrin deposition, extravasation of
neutrophils in the alveolar space and neutrophil mucositis of the
trachea.(Yao et al. 2020; Gu et al. 2005) Bost et al., revealed at least
ten different neutrophil states present in blood and broncho-alveolar
lavage of COVID-19 patients, with resting state phenotype mainly
associated with mild patients and activated or immature phenotype
associated with severe patients.(Bost et al. 2021) Their results
suggested that COVID-19 is associated with a state of ‘immune silence’
(demonstrated by loss of neutrophil and monocyte immunosuppression and
the replacement of lung memory CD8+ T cells by naïve T cells),
correlating with severe clinical manifestation and outcome.(Bost et al.
2021) Diao et al., showed T-cells are dysfunctional with increased
expression of exhaustion molecules related to heightened systemic
inflammation, including IL-6 levels.(Diao et al. 2020) We have
previously shown that IL-6 plays a major role in T-cell dependent Ang-II
thromboinflammatory responses and in the activation and aggregation of
platelets.(Senchenkova, Russell, et al. 2019) These findings support the
hypothesis that drug discovery programmes based on T-cell dependent IL-6
signalling pathways may afford protection against thromboinflammation in
COVID-19.
As observed with other pathological conditions (e.g. sickle cell
disease),(Ansari et al. 2021) NET levels are increased in COVID-19
patients, with sera from COVID-19 patients being shown to trigger NET
release from control neutrophils, and containing increased MPO-DNA
complexes and citrullinated histone H3 levels which correlated with
disease severity.(Veras et al. 2020; Zuo et al. 2020) These results
suggest NETs may contribute to COVID-19 pathology and NET biomarkers may
help to predict clinical worsening and VTE.
Neutrophil degranulation and NET formation exerts various intracellular
danger-associated molecular patterns (DAMPs) activating pattern
recognition receptors (PRRs) on nearby immune and non-immune cells
releasing pro-inflammatory mediators.(Tomar et al. 2020) DAMPs activate
properdin, factor B and C3, all components of the alternative pathway
necessary to induce the complement cascade. Reports have shown increased
activation of the complement system in severe COVID-19 patients.(Holter
et al. 2020) Lung biopsies from COVID-19 patients have shown deposits of
terminal complement components C5b-9, C4d, and mannose binding lectin
(MBL)-associated serine protease (MASP)2, consistent with sustained,
systemic activation of the complement pathways.(Magro et al. 2020) These
findings highlight the therapeutic strategy of complement targeted
therapies for COVID-19 mediated thrombosis.
The initial neutrophil response also leads to interactions with
platelets via a variety of different mechanisms including Mac-1
(CD11b/CD18)/Glycoprotein Ib (CD42) and P-Selectin/P-selectin
glycoprotein ligand-1 (PSGL-1), formation of fibrin cross-links (via
Mac-1/fibrin interaction) and induction of extrinsic TF/Factor IIa
pathway, generating thrombin.(De Meyer et al. 2016) TF-enriched NETs and
a high neutrophil count are associated with increased disease severity
and poor prognosis in COVID-19,(Skendros et al. 2020) amplifying the
need for increased research regarding platelet-neutrophil interactions
in thrombogenesis.