PUBLICATION
Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis
- Authors
- Henderson, S.R., Horsley, H., Frankel, P., Khosravi, M., Goble, T., Carter, S., Antonelou, M., Evans, R.D.R., Zhang, X., Chu, T.Y., Lin, H.H., Gordon, S., Salama, A.D.
- ID
- ZDB-PUB-230223-40
- Date
- 2023
- Source
- Annals of the rheumatic diseases 82(6): 848-856 (Journal)
- Registered Authors
- Carter, Stephen, Khosravi, Maryam
- Keywords
- autoimmune diseases, granulomatosis with polyangiitis, systemic vasculitis
- MeSH Terms
-
- Animals
- Antibodies, Antineutrophil Cytoplasmic
- Giant Cells
- Granuloma/complications
- Granulomatosis with Polyangiitis*/drug therapy
- Interleukin-6
- Leukocytes, Mononuclear
- Microscopic Polyangiitis*
- Myeloblastin
- Peroxidase
- Zebrafish
- PubMed
- 36801813 Full text @ Ann. Rheum. Dis.
Citation
Henderson, S.R., Horsley, H., Frankel, P., Khosravi, M., Goble, T., Carter, S., Antonelou, M., Evans, R.D.R., Zhang, X., Chu, T.Y., Lin, H.H., Gordon, S., Salama, A.D. (2023) Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis. Annals of the rheumatic diseases. 82(6):848-856.
Abstract
Objectives Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation.
Methods We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model.
Results In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor.
Conclusions These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping