Progranulin enhances complement component 5a-primed neutrophil activation in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disorder characterized by vascular inflammation and the activation of neutrophils. Complement component 5a (C5a) is pivotal in neutrophil priming and ANCA-mediated activation. Although progranulin (PGRN) is recognized for its involvement in inflammatory processes, yet its specific role in ANCA-associated vasculitis (AAV) remains poorly understood This study investigates the functional interplay between PGRN and C5a in enhancing neutrophil activation in response to ANCA stimulation.

METHODS

Neutrophils were primed with recombinant PGRN and subsequently stimulated with myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA-positive immunoglobulin G. The respiratory burst was evaluated through dihydrorhodamine oxidation, while degranulation was quantified by measuring lactoferrin release. Additionally, the effects of PGRN-neutralizing antibodies on C5a-primed neutrophils were evaluated.

RESULTS

PGRN significantly upregulated membrane-bound proteinase 3 expression in neutrophils compared to untreated controls (368.0 ± 18.5 vs. 178.0 ± 14.7, p < 0.001) and enhanced MPO release in the culture supernatants (1462.8 ± 202.2 vs. 526.8 ± 118.8, p < 0.001). PGRN-primed neutrophils demonstrated increased respiratory burst activity (p < 0.001) and elevated lactoferrin release (p < 0.001) compared to non-primed cells. Inhibition of PGRN significantly diminished ANCA-mediated oxygen radical production (p < 0.001) and degranulation (p < 0.001) in C5a-primed neutrophils.

CONCLUSIONS

PGRN functionally enhances C5a-mediated neutrophil activation, suggesting a cooperative effect but not a direct molecular interaction. This in vitro study using human neutrophils explores the cooperative effects of PGRN and C5a in ANCA-induced activation. Future research should investigate the use of PGRN inhibitors to mitigate inflammation in AAV.