IgD enhances the release of neutrophil extracellular traps (NETs) via
FcδR in rheumatoid arthritis patients
Abstract
Background and Purpose Neutrophils and the release of neutrophil
extracellular traps (NETs) play important roles in the pathogenesis of
RA. However, IgD, which was abnormally higher in RA, has not been
studied for its pathological role in neutrophil activation and NETs
formation. Experimental Approach Peripheral blood of RA patients and
healthy controls were collected and adjuvant-induced arthritis (AA) rat
models were established. Body weights, the severity of arthritis of AA
rats were monitored regularly. After being stimulated with IgD,
expression of FcδR on neutrophils and NETs formation were analyzed with
multiple approaches such as flow cytometry, scanning electron
microscopy, western blot, and qPCR. IgD-Fc-Ig were used to block
interactions between IgD-FcδR. Additionally, the effect of IgD-induced
neutrophils or NETs on FLS was assayed. Key Results As a specific marker
of NETs, the level of citrullinated histone H3 was positively correlated
with sIgD and FcδR in RA patients. IgD enhances the release of NETs by
activating neutrophils. IgD-Fc-Ig could significantly reduce NETs
formation and FcδR expression on neutrophils in vitro. In vivo,
IgD-Fc-Ig treatment significantly regulates the neutrophil activity and
NETs formation. IgD-Fc-Ig could restrain IgD-induced neutrophil
activation and NETs formation, thus inhibiting FLS proliferation.
Conclusions and Implications Neutrophils were activated by IgD, which
suggests that neutrophils play a role in inducing FLS proliferation in
RA patients who have abnormally higher IgD levels, there by increasing
the severity of the disease. Blocking FcδR inhibited neutrophil
activation and may represent an additional attractive novel therapeutic
strategy for the treatment of RA.