CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis

Rousselle A, Sonnemann J, Amann KU, Mildner A, Lodka D, Kling L, Bieringer M, Schneider U, Leutz A, Enghard P, Kettritz R, Schreiber A (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

DOI: 10.1136/annrheumdis-2021-221984

Abstract

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/EBP beta)(-/-) 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/EBP beta(-/-) 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-1 beta and to promote T(H)17 effector cell polarisation. CSF2rb(-/-) chimeric mice harboured reduced numbers of kidney T(H)17 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 T(H)17 cell polarisation.

Authors with CRIS profile

Kerstin Ute Amann Department of Nephropathology

Involved external institutions

Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) HELIOS Kliniken DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Rousselle, A., Sonnemann, J., Amann, K.U., Mildner, A., Lodka, D., Kling, L.,... Schreiber, A. (2022). CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2021-221984

MLA:

Rousselle, Anthony, et al. "CSF2-dependent monocyte education in the pathogenesis of ANCA-induced glomerulonephritis." Annals of the Rheumatic Diseases (2022).

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