. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature. 2019 Dec 11; PubMed.

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  1. The RIP kinase family evolved as part of a host antiviral response. Specifically, programmed necrosis, aka necroptosis, regulated by RIP kinases, represents a host adaptation to mitigate the effects of Caspase-8-targeted cell death suppressors (as shown in Fig 1 of Kaiser et al., 2013, a helpful review of viral modulation of programmed necrosis).

    RIPK1 signaling is very complex, so it’s not surprising that these authors found genetic variants that skew the immune phenotype away from immunodeficiency and toward an autoinflammatory one. It is also not surprising that the human “host” develops compensatory mechanisms, i.e., downregulation of TNFR1 expression and ROS, to mitigate the vicious cycle of inflammation that would ensue if the hypersensitivity to inflammatory stimuli were left unchecked. It is clearly a cautionary tale that phenotypes in mice may not always predict the human condition.

    The implication of the authors’ successful IL-6-targeting results is that targeting of other pro-inflammatory cytokines, like soluble TNF, may also afford benefit in individuals with this autoinflammatory disease as well as in chronic inflammatory age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s. 

    References:

    . Viral modulation of programmed necrosis. Curr Opin Virol. 2013 Jun;3(3):296-306. Epub 2013 Jun 15 PubMed.

  2. Over the last decade, the RIPK1 protein has been studied intensively. This multifunctional kinase has been shown to play an important role in several signalling pathways underpinning energy homeostasis, inflammatory response, and cell death. Therefore, RIPK1 has become an interesting therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory disorders.

    In this recent article, Tao et al. report two families with RIPK1 mutations (D324V and D324H). Mutation carriers of both families developed recurrent fevers and lymphadenopathy. Here, a strong activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines was observed in a RIPK1-dependent manner.

    Expression of the mutations in mouse fibroblasts showed increased sensitivity to RIPK1-mediated apoptosis but also pro-inflammatory cytokine induction of IL6 and TNF. Patient-derived fibroblasts showed, in contrast, reduced RIPK1 expression and downregulated reactive oxygen production resulting in resistance to necroptosis and ferroptosis.

    Biochemically, the mutations at D324 of the RIPK1 protein led to the production of non-caspase 8-cleavable RIPK1. In so doing, RIPK1 was not cleaved in its RIPK1 kinase domain and its intermediate and death domains. The authors conclude that non-cleavable variants of RIPK1 promote RIPK1 activation, leading to autoinflammatory disease conditions accompanied by an increased sensitivity for necroptosis and apoptosis, but also lead to compensatory mechanisms protecting against several pro-cell death stimuli.

    Although this report does not focus on neurodegeneration, the general mechanism of RIPK1 function and its potential impact in neurodegenerative disorders appears obvious. RIPK1 expression and its possible association with necroptosis have been reported in Alzheimer’s disease (AD) (Caccamo et al., 2017) and amyotrophic lateral sclerosis (ALS) (Re et al., 2014). Moreover, inflammatory events have been reported to be critical in AD, frontotemporal lobar degeneration, etc. (Akiyama et al., 2000; Griffin et al.,1989; Ising et al., 2019). 

    We were recently able to show that the necrosome complex can be detected in granulovacuolar degeneration (GVD) in AD (Koper et al., 2019). GVD is a lesion in the cytoplasm of neurons in the hippocampal formation seen in AD, Parkinson’s disease, ALS cases, etc., and aged individuals. GVD spreads into other brain regions in AD cases and is associated with AD-related neuron loss in the hippocampus and the frontal cortex.

    Given the slow progress in neuron loss over many years in AD despite detection of the active necrosome in GVD lesions, the question arises whether there are protective mechanisms related to the necrosome components pRIPK1, pRIPK3, and pMLKL. The compensatory mechanisms of non-cleaved RIPK1 observed in the carriers of the D324V or D324H mutation may point to potential mechanisms for modulating cell-death speed possibly also in neurodegenerative disorders, explaining the presence of neurons exhibiting the active necrosome without immediately dying.

    That RIPK1 mutations, which disable caspase 8 cleavage of RIPK1, were associated with an autoinflammatory disease may point to a central role of caspase 8-related cleavage of RIPK1 not only for inflammatory diseases but also for neurodegenerative disorders being connected with RIPK1-related cell death forms and neuroinflammation.

    Taken together, this article teaches us that RIPK1, a central player in inflammatory and cell-death pathways, acts deleterious to cells not only in terms of inducing cell death and inflammation but can also induce compensatory mechanisms. Caspase 8 cleavage of RIPK1 appears to play a central role for proper regulation of RIPK1 function. The involvement of RIPK1, its cleavage products, and its possible disease-related functions in neurodegenerative disorders needs further clarification.

    References:

    . Inflammation and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):383-421. PubMed.

    . Necroptosis activation in Alzheimer's disease. Nat Neurosci. 2017 Sep;20(9):1236-1246. Epub 2017 Jul 24 PubMed.

    . Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7611-5. PubMed.

    . NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov;575(7784):669-673. Epub 2019 Nov 20 PubMed.

    . Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease. Acta Neuropathol. 2019 Dec 4; PubMed.

    . Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014 Mar 5;81(5):1001-8. Epub 2014 Feb 6 PubMed.

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