RT Journal Article
SR Electronic
T1 CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1162
OP 1172
DO 10.1136/annrheumdis-2021-221984
VO 81
IS 8
A1 Rousselle, Anthony
A1 Sonnemann, Janis
A1 Amann, Kerstin
A1 Mildner, Alexander
A1 Lodka, Dörte
A1 Kling, Lovis
A1 Bieringer, Markus
A1 Schneider, Udo
A1 Leutz, Achim
A1 Enghard, Philipp
A1 Kettritz, Ralph
A1 Schreiber, Adrian
YR 2022
UL http://ard.bmj.com/content/81/8/1162.abstract
AB Objectives Myeloid cell activation by antineutrophil cytoplasmic antibody (ANCA) is pivotal for necrotising vasculitis, including necrotising crescentic glomerulonephritis (NCGN). In contrast to neutrophils, the contribution of classical monocyte (CM) and non-classical monocyte (NCM) remains poorly defined. We tested the hypothesis that CMs contribute to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and that colony-stimulating factor-2 (CSF2, granulocyte-macrophage colony-stimulating factor (GM-CSF)) is an important monocyte-directed disease modifier.Methods Myeloperoxidase (MPO)-immunised MPO−/− mice were transplanted with haematopoietic cells from wild-type (WT) mice, C–C chemokine receptor 2 (CCR2)−/− mice to abrogate CM, or transcription factor CCAAT–enhancer-binding protein beta (C/EBPβ)−/− mice to reduce NCM, respectively. Monocytes were stimulated with CSF2, and CSF2 receptor subunit beta (CSF2rb)-deficient mice were used. Urinary monocytes and CSF2 were quantified and kidney Csf2 expression was analysed. CSF2-blocking antibody was used in the nephrotoxic nephritis (NTN) model.Results Compared with WT mice, CCR2−/− chimeric mice showed reduced circulating CM and were protected from NCGN. C/EBPβ−/− chimeric mice lacked NCM but developed NCGN similar to WT chimeric mice. Kidney and urinary CSF2 were upregulated in AAV mice. CSF2 increased the ability of ANCA-stimulated monocytes to generate interleukin-1β and to promote TH17 effector cell polarisation. CSF2rb−/− chimeric mice harboured reduced numbers of kidney TH17 cells and were protected from NCGN. CSF2 neutralisation reduced renal damage in the NTN model. Finally, patients with active AAV displayed increased urinary CM numbers, CSF2 levels and expression of GM-CSF in infiltrating renal cells.Conclusions CMs but not NCMs are important for inducing kidney damage in AAV. CSF2 is a crucial pathological factor by modulating monocyte proinflammatory functions and thereby TH17 cell polarisation.Data are available upon reasonable request.