Ferroptosis of CD163
CD163
PC
ferroptosis
lupus nephritis
programmed cell death
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
22
02
2023
accepted:
11
07
2023
medline:
17
8
2023
pubmed:
16
8
2023
entrez:
16
8
2023
Statut:
epublish
Résumé
Dysregulation of cell death and defective clearance of dying cells are closely related to the pathogenesis of lupus nephritis (LN). However, the contribution of a recently discovered form of programmed cell death (PCD) called ferroptosis to LN has not been explored in detail. The purpose of this study was to investigate the role of ferroptosis and its associated metabolic pathways in the pathogenesis of LN. The composite gene expression scores were calculated by averaging the z-scored transformed log2 expressed genes within each form of PCD and pathway. Immunohistochemistry and immunofluorescence assays were used to verify the bioinformatics results. We determined that ferroptosis is prominently and specifically elevated in the glomerular compartment of LN patients compared to other forms of PCD and kidney disease. This finding was then verified by immunohistochemical staining of 4-HNE (a key indicator for ferroptosis) expression in our own cohort (P < 0.0001). Intercorrelation networks were observed between 4-HNE and blood urea nitrogen, SLE disease activity index, serum creatinine, and complement 4, and negatively correlated with glomerular filtration rate in our own LN cohort (P < 0.05). Furthermore, enhanced iron metabolism and reduced fatty acid synthesis may be the most important factors for ferroptosis within the glomerulus. Through analysis of a single cell sequencing dataset and verification of immunohistochemical and immunofluorescence staining, aberrantly activated lipid peroxidation in CD163+ macrophages and CD10+ PC+ (pyruvate carboxylase) epithelial cells indicated that they may be undergoing ferroptosis in the glomerular compartment. Two dysregulated genes, CD163 and PC, were identified and verified that were significantly associated with lipid peroxidation. Targeting ferroptosis in CD163+ macrophages and CD10+ PC+ epithelial cells may provide novel therapeutic approaches in LN.
Sections du résumé
Background
Dysregulation of cell death and defective clearance of dying cells are closely related to the pathogenesis of lupus nephritis (LN). However, the contribution of a recently discovered form of programmed cell death (PCD) called ferroptosis to LN has not been explored in detail. The purpose of this study was to investigate the role of ferroptosis and its associated metabolic pathways in the pathogenesis of LN.
Methods
The composite gene expression scores were calculated by averaging the z-scored transformed log2 expressed genes within each form of PCD and pathway. Immunohistochemistry and immunofluorescence assays were used to verify the bioinformatics results.
Results
We determined that ferroptosis is prominently and specifically elevated in the glomerular compartment of LN patients compared to other forms of PCD and kidney disease. This finding was then verified by immunohistochemical staining of 4-HNE (a key indicator for ferroptosis) expression in our own cohort (P < 0.0001). Intercorrelation networks were observed between 4-HNE and blood urea nitrogen, SLE disease activity index, serum creatinine, and complement 4, and negatively correlated with glomerular filtration rate in our own LN cohort (P < 0.05). Furthermore, enhanced iron metabolism and reduced fatty acid synthesis may be the most important factors for ferroptosis within the glomerulus. Through analysis of a single cell sequencing dataset and verification of immunohistochemical and immunofluorescence staining, aberrantly activated lipid peroxidation in CD163+ macrophages and CD10+ PC+ (pyruvate carboxylase) epithelial cells indicated that they may be undergoing ferroptosis in the glomerular compartment.
Conclusions
Two dysregulated genes, CD163 and PC, were identified and verified that were significantly associated with lipid peroxidation. Targeting ferroptosis in CD163+ macrophages and CD10+ PC+ epithelial cells may provide novel therapeutic approaches in LN.
Identifiants
pubmed: 37583695
doi: 10.3389/fimmu.2023.1171318
pmc: PMC10423811
doi:
Substances chimiques
CD163 antigen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1171318Subventions
Organisme : NIAMS NIH HHS
ID : P30 AR070253
Pays : United States
Informations de copyright
Copyright © 2023 Cheng, Mou, Su, Chen, Zhang, Xie, Xue, Lee, Wu and Du.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Front Oncol. 2021 Jan 07;10:599816
pubmed: 33489900
Clin Immunol. 2017 Dec;185:59-73
pubmed: 27519955
Nucleic Acids Res. 2003 Feb 15;31(4):e15
pubmed: 12582260
Nat Commun. 2022 Feb 3;13(1):676
pubmed: 35115492
Arthritis Rheum. 2012 Aug;64(8):2677-86
pubmed: 22553077
Front Immunol. 2020 Apr 15;11:671
pubmed: 32351512
Ann Rheum Dis. 2018 Aug;77(8):1226-1233
pubmed: 29724730
Sci Adv. 2022 Feb 4;8(5):eabl8920
pubmed: 35108055
Arthritis Rheum. 1997 Sep;40(9):1725
pubmed: 9324032
Apoptosis. 2021 Aug;26(7-8):385-414
pubmed: 34236569
Cell Death Dis. 2022 Jul 14;13(7):608
pubmed: 35835748
Cell. 2012 May 25;149(5):1060-72
pubmed: 22632970
Nat Immunol. 2021 Sep;22(9):1107-1117
pubmed: 34385713
Cell Metab. 2019 Jun 4;29(6):1291-1305.e8
pubmed: 31006591
Cell Rep. 2021 Nov 23;37(8):110037
pubmed: 34818536
Clin Immunol. 2023 Mar;248:109213
pubmed: 36566913
Cell Death Differ. 2004 Oct;11(10):1066-75
pubmed: 15195070
Cell Res. 2021 Feb;31(2):107-125
pubmed: 33268902
Sci Rep. 2022 Nov 5;12(1):18826
pubmed: 36335193
Kidney Int. 2004 Feb;65(2):521-30
pubmed: 14717922
Science. 2003 May 30;300(5624):1439-43
pubmed: 12775843
Curr Mol Med. 2022 May 25;:
pubmed: 35619279
Arthritis Rheumatol. 2016 Nov;68(11):2740-2751
pubmed: 27159593
Nat Rev Dis Primers. 2020 Jan 23;6(1):7
pubmed: 31974366
Science. 2022 Mar 18;375(6586):1254-1261
pubmed: 35298263
Lupus. 2022 Jul;31(8):985-997
pubmed: 35588147
Nat Immunol. 2019 Jul;20(7):902-914
pubmed: 31209404
Cell Death Discov. 2021 Apr 7;7(1):71
pubmed: 33828074