Impact of loss of NF‐κB1, NF‐κB2 or c‐REL on SLE‐like autoimmune disease and lymphadenopathy in Faslpr/lpr mutant mice

Low, Jun T.; Hughes, Peter; Lin, Ann; Siebenlist, Ulrich; Jain, Reema; Yaprianto, Kelvin; Gray, Daniel H.D.; Gerondakis, Steven Demetrious; Strasser, Andreas; O’Reilly, Lorraine A.

doi:10.1038/icb.2015.66

Cited by 17 publications

(14 citation statements)

References 55 publications

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“…Failure to up-regulate anti-apoptotic protein expression upon BCR stimulation, due to defective NF-κB activation in the absence of PKK, may thus likely be responsible for the impaired survival of activated B cells in PKK-deficient Sle mice, which in turn may ultimately lead to the reversal of many lupus features observed in PKK-deficient Sle mice. Consistent with this view, it was recently reported that the loss of NF-κB family members resulted in the amelioration of a SLE-like autoimmune disease in a lupus mouse model [75]. …”

Section: Discussionsupporting

confidence: 54%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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Section: Discussionsupporting

confidence: 54%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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“…3, 46 However, unexpectedly, NF-κB1 signalling has recently been shown to drive the lymphoproliferation in mice deficient in Fas. 47 Necroptosis has been suggested to contribute to the contraction of T cell responses, as cell death in caspase-8 deficient T cells upon T cell receptor ligation is prevented by RIPK1 kinase inhibition or RIPK3 co-deletion. 48 However, recent reports in MLKL and caspase-8 deficient mice show subtle differences in a discrete subset of inflammatory genes, suggesting closer examination of non-necroptotic activities of RIPK3 and RIPK1 is warranted.…”

Section: Crosstalk Between Tlr and Tnfr1 Signalling Pathways: Non-apomentioning

confidence: 99%

Section: Caspase-8-mediated Repression Of Necroptosismentioning

confidence: 99%

Caspase‐8: not so silently deadly

2017

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Apoptosis is a caspase-dependent programmed form of cell death, which is commonly believed to be an immunologically silent process, required for mammalian development and maintenance of cellular homoeostasis. In contrast, lytic forms of cell death, such as RIPK3- and MLKL-driven necroptosis, and caspase-1/11-dependent pyroptosis, are postulated to be inflammatory via the release of damage associated molecular patterns (DAMPs). Recently, the function of apoptotic caspase-8 has been extended to the negative regulation of necroptosis, the cleavage of inflammatory interleukin-1β (IL-1β) to its mature bioactive form, either directly or via the NLRP3 inflammasome, and the regulation of cytokine transcriptional responses. In view of these recent advances, human autoinflammatory diseases that are caused by mutations in cell death regulatory machinery are now associated with inappropriate inflammasome activation. In this review, we discuss the emerging crosstalk between cell death and innate immune cell inflammatory signalling, particularly focusing on novel non-apoptotic functions of caspase-8. We also highlight the growing number of autoinflammatory diseases that are associated with enhanced inflammasome function.

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“…Use of lpr-cREL −/− mice (46) showed that lupus-like disease depends on immune response activation by c-REL, a component of the NF-κB system, whereas absence of NF-κB1 (p65) in lpr mice led to reduced lymphadenopathy. These data argue that hyperactivation is essential for lpr T cell hyperproliferation and corroborate previous results showing that reduction in DN cell activity leads to reduced lymphadenopathy (17).…”

Section: Etiology Of In Vivo Lpr T Cell Proliferationmentioning

confidence: 99%

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

et al. 2017

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Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

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Impact of loss of NF‐κB1, NF‐κB2 or c‐REL on SLE‐like autoimmune disease and lymphadenopathy in Fas^lpr/lpr mutant mice

Cited by 17 publications

References 55 publications

PKK deficiency in B cells prevents lupus development in Sle lupus mice

PKK deficiency in B cells prevents lupus development in Sle lupus mice

Caspase‐8: not so silently deadly

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

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