Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation

Guo, Chaohuan; Fu, Rong; Zhou, Mianjing; Wang, Shuang; Huang, Yuefang; Hu, Haoqiang; Zhao, Jijun; Gaskin, Felicia; Yang, Niansheng; Fu, Shu Man

doi:10.1016/j.jaut.2019.05.014

Cited by 114 publications

(104 citation statements)

References 29 publications

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“…We surprisingly found that MLKL mRNA was obviously upregulated in the PBMCs of LN patients when compared with patients without LN (p < 0.005). To date, only one paper reported the correlation of necroptosis with LN, showing that PIPK3 and MLKL were activated in podocytes in renal biopsies from patients with LN [11]. Whether there is a crosstalk between the renal parenchymal cells and peripheral blood cells in necroptosis process still needs to be analyzed.…”

Section: Discussionmentioning

confidence: 99%

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Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement, and SLE disease activity

Zhang

Jie

et al. 2020

Arthritis Res Ther

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Background Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis; however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. Methods Real-time transcription-polymerase chain reaction (RT-PCR) analysis was used to determine the expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA), and 30 age- and sex-matched healthy controls (HC). Spearman’s correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value. Results Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for antinuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r = 0.3577, p = 0.0237), erythrocyte sedimentation rate (ESR) (r = 0.4091, p = 0.0043), serum immunoglobulin G (IgG) concentration (r = 0.3546, p = 0.0289), and the numbers of positive antinuclear antibodies (ANAs) (r = 0.3945, p = 0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779–0.9775, p < 0.001) to discriminate SLE from controls. Conclusions These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.

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Section: Discussionmentioning

confidence: 99%

“…The phosphorylated MLKL inserts itself into the cell membrane, disrupts its integrity, and leads to cell death [9]. Various studies have revealed that necroptosis could be implicated in the pathogenesis of many inflammatory and autoimmune diseases, including SLE [6,10,11].…”

Section: Introductionmentioning

confidence: 99%

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement, and SLE disease activity

Zhang

Jie

et al. 2020

Arthritis Res Ther

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“…In an experimental model of LN, they found a close relationship between NLRP3 activation and the occurrence of proteinuria [84]. Guo et al highlighted the potential role of necroptosis in podocytes, with their identification of RIP3 as an activator of the NLRP3 inflammasome pathway [85]. The inhibition of RIP3-dependent necroptosis in a lupus-prone model resulted in lower proteinuria and a lower severity of glomerular lesions, together with NLRP3 inflammasome inhibition [85].…”

Section: Podocytes As Immune Cellsmentioning

confidence: 99%

“…Guo et al highlighted the potential role of necroptosis in podocytes, with their identification of RIP3 as an activator of the NLRP3 inflammasome pathway [85]. The inhibition of RIP3-dependent necroptosis in a lupus-prone model resulted in lower proteinuria and a lower severity of glomerular lesions, together with NLRP3 inflammasome inhibition [85]. These findings strongly suggest that the necroptosis pathway is involved in podocyte NLRP3 activation.…”

Section: Podocytes As Immune Cellsmentioning

confidence: 99%

Podocyte Injury in Lupus Nephritis

Sakhi

Moktefi

Bouachi

et al. 2019

JCM

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Systemic lupus erythematosus (SLE) is characterized by a broad spectrum of renal lesions. In lupus glomerulonephritis, histological classifications are based on immune-complex (IC) deposits and hypercellularity lesions (mesangial and/or endocapillary) in the glomeruli. However, there is compelling evidence to suggest that glomerular epithelial cells, and podocytes in particular, are also involved in glomerular injury in patients with SLE. Podocytes now appear to be not only subject to collateral damage due to glomerular capillary lesions secondary to IC and inflammatory processes, but they are also a potential direct target in lupus nephritis. Improvements in our understanding of podocyte injury could improve the classification of lupus glomerulonephritis. Indeed, podocyte injury may be prominent in two major presentations: lupus podocytopathy and glomerular crescent formation, in which glomerular parietal epithelial cells play also a key role. We review here the contribution of podocyte impairment to different presentations of lupus nephritis, focusing on the podocyte signaling pathways involved in these lesions.

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“…The phosphorylated MLKL inserts itself into the cell membrane, disrupts its integrity and leads to cell death [9]. Various studies have revealed that necroptosis could be implicated in the pathogenesis of many in ammatory and autoimmune diseases, including SLE [6,10,11].…”

Section: Introductionmentioning

confidence: 99%

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

Zhang

Jie

et al. 2020

Preprint

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Background: Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis, however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. Methods: Real-time transcription-polymerase chain reaction analysis (RT-PCR) was used to determine expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA) and 30 age- and sex-matched healthy controls(HC). Spearman's correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic curve (ROC) was created to evaluate the diagnostic value. Results: Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for anti-nuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r=0.3577, p=0.0237), erythrocyte sedimentation rate (ESR) (r=0.4091, p=0.0043), serum immunoglobulin G (IgG) concentration (r=0.3546, p=0.0289) and the numbers of positive antinuclear antibodies (ANAs) (r=0.3945, p=0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779 - 0.9775, p<0.001) to discriminate SLE from controls.Conclusions: These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.

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Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation

Cited by 114 publications

References 29 publications

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement, and SLE disease activity

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement, and SLE disease activity

Podocyte Injury in Lupus Nephritis

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

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