RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

Ito, Yasushi; Ofengeim, Dimitry; Najafov, Ayaz; Das, Sudeshna; Saberi, Shahram; Liu, Ying; Hitomi, Junichi; Zhu, Hong; Chen, Hongbo; Mayo, Lior; Geng, Jiefei; Amin, Palak; DeWitt, Judy Park; Mookhtiar, Adnan K.; Florez, Marcus A.; Ouchida, Amanda Tomie; Fan, Jie; Pasparakis, Manolis; Kelliher, Michelle A.; Ravits, John; Yuan, Junying

doi:10.1126/science.aaf6803

Cited by 493 publications

(595 citation statements)

References 40 publications

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“…Astrocytes release TNF-α, FasL, and TRAIL, which can trigger necroptosis through RIPK1 and MLKL activation, and this mechanism has been demonstrated in murine models of ALS (6). RIPK1-mediated axonal pathology was observed in pathological specimens from ALS patients (7). Necroptotic mechanisms were also observed in MS pathological samples (8).…”

Section: Mechanisms Of Neurodegenerationmentioning

confidence: 82%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

386

240

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Section: Mechanisms Of Neurodegenerationmentioning

confidence: 82%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

386

240

View full text Add to dashboard Cite

“…In iWAT, seven of the 61 cytokines/chemokines showed a significant change in their expression with age and DR altered the expression of only three cytokines/chemokines (Figure 2b, right panel and Table S1). The data in Figure 2c show that the transcript levels of the pro‐inflammatory cytokines IL‐6, TNF‐α, and IL‐1β, which are strong predictors of mortality and chronic diseases in elderly humans (Singh & Newman, 2011) and have been shown to be induced by necroptosis (Ito et al., 2016), are significantly increased in eWAT from old mice 3.9‐, 4.7‐, and 5.1‐fold, respectively, and are attenuated by DR.…”

mentioning

confidence: 92%

“…Phosphorylated MLKL (P‐MLKL) oligomerizes, binds to, and ruptures the cell membrane, resulting in the release of cellular components including DAMPs. Several studies show that blocking necroptosis either genetically or pharmacologically dramatically reduces inflammation in a variety of mouse models (Ito et al., 2016; Meng et al, 2015). In addition, blocking/reducing necroptosis appears to have an impact on the aging of the male reproductive system (Li et al., 2017) and increases the lifespan of ApoE knockout mice (Meng et al., 2015) and G93A transgenic mouse model of ALS (Ito et al., 2016).…”

mentioning

confidence: 99%

Necroptosis increases with age and is reduced by dietary restriction

et al. 2018

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SummaryNecroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated MLKL and RIPK3, markers of necroptosis, were increased 2.7‐ and 1.9‐fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P‐MLKL and P‐RIPK3 to levels similar to adult mice. An increase in the expression of RIPK1 (1.6‐fold) and MLKL (2.7‐fold), not RIPK3, was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro‐inflammatory cytokines IL‐6 (3.9‐fold), TNF‐α (4.7‐fold), and IL‐1β (5.1‐fold)], and 11 chemokines in old mice. DR attenuated the expression of IL‐6, TNF‐α, and IL‐1β as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P‐MLKL and MLKL or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro‐inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age.

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“…Recently, Re et al [32] and Ito et al [34] found that necroptosis may be involved in the MN death. This finding provides an important connection between neurodegeneration and previously observed abnormal inflammation/immune response in ALS.…”

Section: Necroptosis and Immune Dysfunctionmentioning

confidence: 99%

“…Recently, Cirulli et al [33] compared the whole exome sequences between ALS and control, and found that the non-canonical IκB kinase family TANK-binding kinase 1 (TBK1) was a gene associated with ALS by interacting with ALS-related proteins, optineurin (OPTN) and p62. Furthermore, Ito et al [34] demonstrated that OPTN inhibited dysmyelination and axonal degeneration through suppressing receptorinteracting kinase 1 (RIPK1) and the downstream subsets are preferentially elicited in ALS has been elusive. Recently, several studies support that the programmed necrosis (necroptosis), a new type of cell death, is present in ALS.…”

Section: Necroptosis and Its Implications In Alsmentioning

confidence: 99%

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Liu¹,

Zheng²,

Xin³

et al. 2017

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How to cite this article: Liu JF, Zheng OX, Xin JG, Chen HH, Xin JJ. How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis ? Neuroimmunol Neuroinflammation 2017;4:109-16. Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1 G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1 G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte MinireviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

Cited by 493 publications

References 40 publications

CNS inflammation and neurodegeneration

CNS inflammation and neurodegeneration

Necroptosis increases with age and is reduced by dietary restriction

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

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