Cardiovascular risk in ANCA-associated vasculitis: monocyte phenotyping reveals distinctive signatures between serological subsets

Abstract

Objectives: Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is associated with an increased cardiovascular risk, particularly the myeloperoxidase AAV serotype (MPO-AAV). Distinct alterations in monocyte phenotypes may cause accelerated atherosclerotic disease in AAV. Methods: A cohort including 43 AAV patients and 19 healthy controls were included for downstream analyses. Extensive phenotyping of monocytes and monocyte-derived macrophages was performed using bulk RNA-sequencing and flow cytometry. An in vitro transendothelial migration assay reflecting intrinsic adhesive and migratory capacities of monocytes was employed. Subsequent sub-analyses were performed to investigate differences between serological subtypes. Results: Monocyte subset analysis showed increased classical monocytes during active disease, whereas non-classical monocytes were decreased. RNA-sequencing revealed upregulation of distinct inflammatory pathways and lipid metabolism-related markers in monocytes of active AAV patients. No differences were detected in the intrinsic monocyte adhesion and migration capacity. Monocytes of MPO-AAV patients in remission expressed genes related to inflammation, coagulation, platelet-binding and interferon signalling, whereas the expression of chemokine receptors indicative of acute inflammation and monocyte extravasation (i.e., CCR2 and CCR5) was increased in monocytes of proteinase-3(PR3)-AAV patients. During active disease, PR3-AAV was linked with elevated serum CRP and increased platelet counts compared to MPO-AAV. Conclusion: These findings highlight changes in monocyte subset composition and activation, but not in the intrinsic migration capacity of AAV monocytes. MPO-AAV monocytes are associated with sustained upregulation of inflammatory genes, whereas PR3-AAV monocytes exhibit chemokine receptor upregulation. These molecular changes may play a role in elevating cardiovascular risk as well as in the underlying pathophysiology of AAV.

Infiltrative classical monocyte-derived andSPP1lipid-associated macrophages mediate inflammation and fibrosis in ANCA-associated glomerulonephritis

“…PR3-ANCA generally have a higher risk of relapses 3 and had higher S100A9 + classical macrophage infiltration, whereas kidney involvement is more frequent in MPO-ANCA vasculitis 3 and classical MDMs of MPO-AGN patients showed higher interferon responses compared to PR3-AGN. Since peripheral blood monocytes of MPO-AAV patients show a similar upregulation of interferon responses (data submitted 61 ), observations could represent actual pathological distinctions specific to different serotypes, rather than variations related to the stages of the disease. However, the limited sample size and heterogeneity of the samples included in our study precluded a more in-depth investigation of these potential causes, further research investigating serotype-specific effects are needed.…”