The Role of Inflammasomes in Glomerulonephritis
Abstract
:1. The Inflammasome
2. NLR Family Inflammasomes
2.1. NLRP Subfamily
2.2. IPAF-NAIP Subfamily
3. Non-NLR Family Inflammasomes
4. Mechanisms of NLRP3 Inflammasome Activation
5. Inflammasome Effector Functions
6. The Role of the Inflammasome in Adaptive Immunity and Autoimmunity
7. Inflammasome Involvement in Autoimmune Kidney Diseases
7.1. Lupus Nephritis
7.1.1. In Vitro Model
7.1.2. Animal Model
7.1.3. Human Model
7.2. ANCA Glomerulonephritis
7.2.1. In Vitro Model
7.2.2. Animal Model
7.2.3. Human Model
7.3. IgA Nephropathy
7.3.1. Animal Model
7.3.2. Human/In Vitro Model
7.4. Anti-Glomerular Basement Membrane Glomerulonephritis
Animal Model
8. Final Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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LUPUS NEPRHITIS | |
Significant Findings | References |
IN VITRO MODEL | |
LL-37: | |
LDGs have the capacity to produce NETs which increase the externalization of immunostimulatory proteins and autoantigens as LL-37, IL-17 and dsDNA. Kidneys from SLE patients are infiltrated by netting neutrophils which show LL-37 and dsDNA explaining the role of aberrant lupus neutrophils the pathogenic role of NETs. | Villanueva et al., Journal of Immunology, 2011. |
NLRP3 is activated by NETs and the expression of the NETs-associated protein LL-37. This stimulus contributes to the production of IL1β and IL-18 causing NETosis. | Kahlenberg et al., Journal of immunology, 2013. |
Expression of axis’s inflammasome: | |
Isolated fresh monocytes from SLE patients increased inflammasome activation described by the elevated expression of Caspase-1, IL-1β and IL-18. | Perez-Alamino et al., Reumatologia Clinica, 2021. |
ANIMAL MODEL | |
P2X7: | |
Increased expression of P2X7 has been observed in kidney biopsies from patients with SLE. | TTurner et al., Nephrology, dialysis, transplantation, 2007. |
Upregulation of P2X7/NLRP3 in kidneys of MRL/lpr mice associates an increase in IL-1β and renal damage developing LN.P2X7 inhibition decreases autoantibodies and immune complexes deposited in the kidneys. | Zhao et al., Arthritis Rheumatology, 2013. |
NFκB and NLPR3: | |
The inhibition of NFκB and NLPR3 by Bay11-7082 in MRL/lpr mice reduces nephritis, the levels of IL-1β, TNF-α and anti-dsDNA and the deposition of immune complexes. | Zhao et al., International Immunopharmacology, 2013. |
AIM2: | |
AIM2 is augmented in macrophages induced by lymphocyte-derived apoptotic DNA. Its knock-down by siRNA ameliorates infiltration of macrophages in tissues. | Zhang et al., Journal of Clinical Immunology, 2013. |
p202 limits AIM2. This increases INF causing susceptibility to murine lupus. | Yin et al., Cell reports, 2014. |
Caspasa-1: | |
The caspase-1 −/− mouse model exposed to pristane protected against the development of autoantibodies related to SLE, nephritis and the action of type I INF. | Kahlenberg et al., Arthritis and Rheumatology, 2014. |
HMGB1: | |
Blocking HMGB1 in BXSB mice reduces the machinery of NLPR3 and improves renal inflammation. | Zhang et al., Scandinavian Journal of immunology, 2014. |
HUMAN MODEL | |
NLRP1: | |
The NLRP1 rs2670660 and NLRP1 rs12150220-rs2670660 A-G haplotype polymorphisms were associated with SLE and the event of nephritis, arthritis and rash. | Pontillo et al., Autoimmunity, 2012. |
NLPR3, NLRP1, Caspasa-1, AIM2: | |
The variant rs10754558 NLRP3 was more common in SLE patients with nephritis. The stimulus with LPS+ATP generated the expression of NLRP1, AIM2, CASP1 and IL1β genes, indicating that NLRP1 is responsible for the IL-β production reflected in monocytes. | da Cruz et al., Immunogenetics, 2020. |
ANCA GLOMERULONEPHRITIS | |
Significant Findings | References |
IN VITRO MODEL | |
IL-18: | |
Il-18 expression is upregulated in patients with ANCA vasculitis. | Hewins et al., Kidney International, 2006. |
ANIMAL MODEL | |
NPS: | |
NE-/PR3- mice in anti-MPO antibody-induced model reduce local cytokines and induction of NCGN. | Schreiber et al., Journal of the American Society of Nephrology, 2012. |
NADPH oxidase: | |
An antibody-mediated anti-MPO model, gp91phox-deficient or p47phox-deficient mice had worsening NCGN. Gp91phox-deficient/caspase-1 double-deficient mice improved NCGN, suggesting that Phox limits the activity of caspase-1 and thus of the inflammasome. | Schreiber et al., Journal of the American Nephrology, 2015. |
HUMAN MODEL | |
IL-18: | |
IL-18 is elevated in the serum from patients diagnosed with ANCA vasculitis compared to healthy controls. The increase in IL-18 is regardless of MPO/PR3 levels. | Hultren et al., Autoimmunity, 2007. |
NLRP3, NOD2, NLRC5: | |
The investigators glimpsed the role of NLRP3 in the tubulointerstitial compartment and the correlation of IL-1β levels with the severity of tubulointerstitial injury in the glomerulus. | Tashiro et al., Clinical Nephrology, 2016. |
NOD2, NLRP3 and NLRC5 were mostly expressed in podocytes and in infiltrating monocytes and macrophages, but barely expressed in glomeruli. | Wang et al., Journal of Translational Medicine, 2019. |
IGA NEPHROPATHY | |
Significant Findings | References |
ANIMAL MODEL | |
IL-1ra: | |
The use of Il-1 receptor antagonist in a IgAN’s mouse model (ddY mice) ceases the exacerbation of the disease. | Chen et al., American Journal of Kidney Diseases, 1997. |
HUMAN/IN VITRO MODEL | |
NLRP3 was mostly expressed in the tubules with no staining in the glomerulus of normal kidneys. Nevertheless, in patients with IgAN, NLRP3 expression was detected in the glomerulus, though it was more increased in the tubules. In human kidney biopsies and in low passage human cells, they established that NLRP3 was decreased during tubular damage. Equally the immunostaining results and the NLRP3 mRNA expression confirmed the presence of NLRP3 and its subsequent loss after renal injury. | Chun et al., Scientific reports, 2016. |
IgAN knockout NLRP3 mice model was generated. The production of IgA immune complexes was inhibited by knockout mice. NLRP3 knockout mice and the kidney-targeting delivery of shRNA of NLRP3 improve renal function. | Tsai et al., scientific reports, 2017. |
ANTIGLOMERULAR BASEMENT MEMBRANE GLOMERULONEPHRITIS | |
Significant Findings | References |
ANIMAL MODEL | |
IL-1ra: | |
IL-1ra protects against clinical and histological worsening in a rat anti-GBM model. | Lan et al., Kidney International, 1993. |
In a rat anti-GBM model, IL-1ra diminishs proteinuria and the expression of adhesion molecules of PMN, such as ICAM-1. | Tang et al., The Journal of Clinical Investigation, 1994. |
IL-18 and IL-12p40: | |
Anti-GBM mice model with IL-12p40−/−, IL-18−/− and both IL-12p40−/− and IL-18 demonstrate IL-12p40 as a crucial cytokine chain in nephritogenic Th1 responses and IL-18 as a proinflammatory local (renal) cytokine. | Kitching et al., Journal of the American Society of Nephrology, 2005. |
IL-1βand IL-1RI: | |
An anti-GBM IL-1β −/− and IL-1RI −/− mouse model was formed. IL-1β −/− mice demonstrated a reduction in crescent formation and cell recruitment. IL-1RI −/− mice presented less serum titers antibodies, less proteinuria and reduced serum creatinine. | Timoshanko et al., Journal of the American Society of Nephrology, 2004. |
Anti-GBM nephritis develops independently of the NLRP3-caspase-1 axis due to the inability of glomerular cells to generate IL-1β. | Lichtnekert et al., Plos One, 2011. |
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Anton-Pampols, P.; Diaz-Requena, C.; Martinez-Valenzuela, L.; Gomez-Preciado, F.; Fulladosa, X.; Vidal-Alabro, A.; Torras, J.; Lloberas, N.; Draibe, J. The Role of Inflammasomes in Glomerulonephritis. Int. J. Mol. Sci. 2022, 23, 4208. https://doi.org/10.3390/ijms23084208
Anton-Pampols P, Diaz-Requena C, Martinez-Valenzuela L, Gomez-Preciado F, Fulladosa X, Vidal-Alabro A, Torras J, Lloberas N, Draibe J. The Role of Inflammasomes in Glomerulonephritis. International Journal of Molecular Sciences. 2022; 23(8):4208. https://doi.org/10.3390/ijms23084208
Chicago/Turabian StyleAnton-Pampols, Paula, Clara Diaz-Requena, Laura Martinez-Valenzuela, Francisco Gomez-Preciado, Xavier Fulladosa, Anna Vidal-Alabro, Joan Torras, Núria Lloberas, and Juliana Draibe. 2022. "The Role of Inflammasomes in Glomerulonephritis" International Journal of Molecular Sciences 23, no. 8: 4208. https://doi.org/10.3390/ijms23084208