PMID- 35418479
OWN - NLM
STAT- MEDLINE
DCOM- 20220714
LR  - 20220802
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Print)
IS  - 0003-4967 (Linking)
VI  - 81
IP  - 8
DP  - 2022 Aug
TI  - CSF2-dependent monocyte education in the pathogenesis of ANCA-induced 
      glomerulonephritis.
PG  - 1162-1172
LID - 10.1136/annrheumdis-2021-221984 [doi]
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/EBPbeta)(-/-) 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/EBPbeta(-/-) 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-1beta 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.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Rousselle, Anthony
AU  - Rousselle A
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany.
FAU - Sonnemann, Janis
AU  - Sonnemann J
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany.
AD  - Nephrology and Medical Intensive Care Medicine, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
FAU - Amann, Kerstin
AU  - Amann K
AD  - Department of Nephropathology, University Hospital Erlangen, 
      Friedrich-Alexander-University (FAU) Erlangen-Nurnberg, Erlangen, Germany.
FAU - Mildner, Alexander
AU  - Mildner A
AD  - Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), 
      Berlin, Germany.
FAU - Lodka, Dorte
AU  - Lodka D
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany.
FAU - Kling, Lovis
AU  - Kling L
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany.
AD  - Nephrology and Medical Intensive Care Medicine, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
FAU - Bieringer, Markus
AU  - Bieringer M
AD  - Department of Cardiology and Nephrology, HELIOS Klinik Berlin-Buch, Berlin, 
      Germany.
FAU - Schneider, Udo
AU  - Schneider U
AUID- ORCID: 0000-0002-9117-3307
AD  - Department of Rheumatology and Clinical Immunology, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
FAU - Leutz, Achim
AU  - Leutz A
AD  - Max Delbruck Center for Molecular Medicine in the Helmholtz Association (MDC), 
      Berlin, Germany.
FAU - Enghard, Philipp
AU  - Enghard P
AUID- ORCID: 0000-0002-7254-3931
AD  - Nephrology and Medical Intensive Care Medicine, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
FAU - Kettritz, Ralph
AU  - Kettritz R
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany.
AD  - Nephrology and Medical Intensive Care Medicine, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
FAU - Schreiber, Adrian
AU  - Schreiber A
AUID- ORCID: 0000-0003-1244-6379
AD  - Experimental and Clinical Research Center, Max Delbruck Center for Molecular 
      Medicine in the Helmholtz Association (MDC) and Charite - Universitatsmedizin 
      Berlin, Corporate Member of Freie Universitat Berlin and Humboldt-Universitat zu 
      Berlin, Berlin, Germany adrian.schreiber@charite.de.
AD  - Nephrology and Medical Intensive Care Medicine, Charite-Universitatsmedizin 
      Berlin, Berlin, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220413
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Antibodies, Antineutrophil Cytoplasmic)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 1.11.1.7 (Peroxidase)
SB  - IM
MH  - Animals
MH  - *Anti-Neutrophil Cytoplasmic Antibody-Associated 
      Vasculitis/complications/pathology
MH  - Antibodies, Antineutrophil Cytoplasmic
MH  - *Glomerulonephritis/etiology/pathology
MH  - *Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
MH  - Mice
MH  - *Monocytes/metabolism
MH  - Peroxidase
PMC - PMC9279749
OTO - NOTNLM
OT  - Autoantibodies
OT  - Autoimmune Diseases
OT  - Granulomatosis with polyangiitis
OT  - Inflammation
OT  - Systemic vasculitis
COIS- Competing interests: None declared.
EDAT- 2022/04/15 06:00
MHDA- 2022/07/15 06:00
PMCR- 2022/07/14
CRDT- 2022/04/14 05:18
PHST- 2021/12/10 00:00 [received]
PHST- 2022/04/01 00:00 [accepted]
PHST- 2022/04/15 06:00 [pubmed]
PHST- 2022/07/15 06:00 [medline]
PHST- 2022/04/14 05:18 [entrez]
PHST- 2022/07/14 00:00 [pmc-release]
AID - annrheumdis-2021-221984 [pii]
AID - 10.1136/annrheumdis-2021-221984 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2022 Aug;81(8):1162-1172. doi: 10.1136/annrheumdis-2021-221984. 
      Epub 2022 Apr 13.