Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation

Zhao, Jijun; Zhang, Hui; Huang, Yuefang; Wang, Hongyue; Wang, Shuang; Zhao, Chun‐Mei; Liang, Yong; Yang, Niansheng

doi:10.1016/j.intimp.2013.05.027

Cited by 101 publications

(73 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sester, manuscript in preparation). Earlier published work implicated NLRP3 in kidney damage in various scenarios, including lupus (30,31,61), and from this work it would be reasonable to propose that the lack of NLRP3 in NZB protects them from kidney pathology seen in the NZB3NZW F1 mice. The contradictory results of Lech et al (34) suggest that such assumptions on the role of NLRP3 require testing in this model.…”

Section: Discussionmentioning

confidence: 62%

“…Human genome-wide association studies have suggested the inflammasome initiator NLRP3 may play a role in type I diabetes in a Brazilian population (27), and one study showed lowered expression of NLRP3 was associated with Crohn's disease (28), although this has not been replicated (29). Experiments in mice have suggested that the NLRP3 inflammasome is activated in kidney during lupus nephritis in two mouse models of SLE: NZB3NZW F1 (first-generation cross between New Zealand Black [NZB] and New Zealand White [NZW] mice) and MRL/Fas lpr (Murphy Roths Large with lymphoproliferation lpr mutation of Fas) (30,31) and may contribute to kidney damage. Lupus-like disease can be induced in nonsusceptible mice by injection of pristane, a mineral oil that induces cell death and elevated IL-1b for at least a month after injection (32).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Sester

Sagulenko

Thygesen

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1β output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.

show abstract

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Sester

Sagulenko

Thygesen

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…However, only whole kidney lysates were analyzed, which does not specifically localize the site of inflammasome activity within the kidney or exclude the contribution of circulating macrophages. This group using similar experimental methods previously determined that administration of Bay11-7082, an inhibitor of the phosphorylation of the inhibitor of NF-κB (IκB), attenuated murine lupus nephritis and resulted in reduced macrophage infiltration, NLRP3 inhibition, and improved survival [27]. In the NZB/W F1 murine model of lupus nephritis, an antagonist of Toll-like receptors 7, 8, and 9 reduced glomerular injury and interstitial inflammation with decreased transcription of both IL-1β and NLRP3 in the kidney [28].…”

Section: Nlrp3 and Glomerular Diseasementioning

confidence: 99%

The emerging role of the inflammasome in kidney diseases

Chang

Ko²,

Clark³

2014

Current Opinion in Nephrology and Hypertension

View full text Add to dashboard Cite

Purpose of review This review focuses on the latest data that elucidates the role of the NLRP3 inflammasome in kidney diseases. Recent findings The NLRP3 inflammasome is not limited by traditional microbial stimuli of innate immunity and its connection with autophagy, apoptosis, fibrosis, and pro-inflammatory cytokines has broader implications for a variety of kidney diseases. In a wide spectrum of glomerular and tubulointerstitial diseases, the NLRP3 inflammasome is upregulated in both classical immune cells such as infiltrating macrophages and resident dendritic cells as well as in renal tubular epithelial cells, and even podocytes. Inhibition of the NLRP3 inflammasome ameliorates renal injury in a variety of animal models. Interestingly, this extends to models of proteinuria, which suggests that the deleterious effect of albuminuria on the proximal tubular epithelium and podocytes is, in part, mediated by inflammasome activation. Summary Recent studies in animal models, and still limited studies in humans, suggest a broad role for inflammasome activation in renal disease. Surprisingly, individual components of the inflammasome, independent of inflammasome activation, may also contribute to progressive renal injury. Additional, studies are needed to define the relative importance of the inflammasome in specific diseases and the therapeutic opportunities afforded by targeting the inflammasome.

show abstract

“…This was supported by studies that alternate-day fasting is neuro-protective and cardio-protective against age-induced inflammation by inhibiting NF-κB and MAPK activation and oxidative damage via inhibition of the DNA binding activity of NF-κB and activator protein 1 (AP-1) (Castello et al, 2010;Jung et al, 2009;Tajes et al, 2010). Consequently, the NF-κB and MAPK signaling pathways may induce the expression of NLRP1 and NLRP3 inflammasome proteins and the precursors of IL-1β and IL-18 under ischemic conditions (Bauernfeind et al, 2009;Liu et al, 2004;Zhao et al, 2013). Our previous findings indicate that cerebral ischemia increased the expression of NLRP1 and NLRP3 inflammasome proteins and precursors of IL-1β and IL-18, and increased inflammasome activation demonstrated by an accumulation of cleaved caspases 1 and 11, and mature IL-1β and IL-18 (Fann et al, 2013a).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of Notch1-mediated neuronal cell death in ischemic stroke

Cheng¹

View full text Add to dashboard Cite

Stroke is a devastating neurological disease with high mortality rate and has profound implications for health economics and resources globally. There is a sense of urgency for scientists to discover a pharmacological target in stroke that could modulate multiple molecular cell injury mechanisms since many therapeutic agents that targeted only a single injury mechanism result in disappointing outcomes in human clinical trials. During stroke, cerebral ischemia triggers a number of membrane bound receptor-mediated signaling cascades that can activate many downstream kinases and transcription factors known to induce neuronal apoptosis. The activation of the membrane receptor Notch1 and its signaling pathway is seen in the infarcted brain, which is shown to deteriorate the outcome of ischemic stroke.Notch1 is a transmembrane receptor that regulates cell fate decisions in the developing nervous system and adult brain. Binding of Notch's ligands leads to the proteolytic cleavage of Notch1 by γ-secretase and the generation of Notch1 intracellular domain (NICD1), which is able to translocate to the nucleus and regulate transcription of its downstream genes. Although Notch1 has been demonstrated to worsen stroke outcome by stimulating the infiltration of pro-inflammatory leukocytes and microglia-induced inflammatory responses, the molecular mechanisms of Notch1 in neurons following ischemic stroke in the induction of pro-apoptotic cascades are still not yet fully established.The present studies aim to investigate the role of γ-secretase-mediated Notch signaling pathway in the induction of neuronal cell death through its modulation with the nuclear factor-κB (NF-κB) pathway, the collaboration with hypoxia-inducible factor-1α (HIF-1α) pathway, and its contribution to the mitogen activated protein kinase (MAPK) pathway, which are all crucial in the induction of neuronal apoptosis. It also aims to observe the modulation of the pro-apoptotic proteins that are activated as a result of Notch1 activation in neurons following ischemic stroke.The present studies demonstrate that the inhibition of Notch1 activation using γ-secretase inhibitors protect neuronal cells against ischemia-induced cell death by targeting an apoptotic marker, cleaved caspase-3, NF-κB subunits p65, p50 and pro-apoptotic BH3-only protein, Bcl-2 interacting mediator of cell death (Bim). In addition, treatment of mice with the γ-secretase inhibitor reduces NICD1, phosphorylated-p65 and Bim expression levels, with reduced infarct size and improved functional outcome in a mouse model of focal ischemic stroke. These findings II suggest that γ-secretase-mediated Notch signaling endangers neurons after ischemic stroke by modulating the NF-κB-Bim pathway.Additional findings suggest that the HIF-1α pathway, a global regulation pathway of cellular response to hypoxia, is able to interact with Notch1 and modulate its signaling during ischemic stroke. Treatment with either a HIF-1α inhibitor or a γ-secretase inhibitor protects neurons against ischemic stress and...

show abstract

Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation

Cited by 101 publications

References 33 publications

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

The emerging role of the inflammasome in kidney diseases

Molecular mechanisms of Notch1-mediated neuronal cell death in ischemic stroke

Contact Info

Product

Resources

About