Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve Injury

Ying, Zhengxin; Pan, Chenjie; Shao, Tianyu; Liu, Liqing; Li, Lin; Guo, Dejia; Zhang, Sitao; Yuan, Tianyi; Cao, R.; Jiang, Zhaodi; Chen, She; Wang, Fengchao; Wang, Xiaodong

doi:10.1016/j.molcel.2018.09.011

Cited by 73 publications

(103 citation statements)

References 41 publications

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“…In contrast, lack of MLKL protein delayed demyelination in CPZ-induced demyelination, indicating that even in this chemically induced disease model, MLKL is involved in the demyelination process, as it is in sciatic nerve injury as previously reported. This result is consistent with a previous study from our laboratory that RIPA-56 cannot block the MLKL-mediated PNS demyelination process induced by injury (12).…”

Section: Discussionsupporting

confidence: 94%

“…However, since MS is a chronic disease with potentially multiple triggering factors, it is not surprising that a necroptosis marker, such as RIP3-mediated phosphorylation of MLKL, has been detected in the diseased tissues, as reported previously (8). Complicating the issue is the fact that MLKL also has a nonnecroptosis function in demyelination (12). The eventual clarification of this issue may have to wait for the development of a demyelination-specific biomarker of MLKL activation (i.e., a specific antibody against the phosphorylated serine 441 site).…”

Section: Discussionmentioning

confidence: 71%

“…Steps. We recently discovered that MLKL, a protein known to rupture cell membranes during necroptotic cell death (9), is induced following sciatic nerve injury and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown (12). We showed that unlike the situation in necroptosis, during which MLKL must be activated by phosphorylation mediated by RIP3, the function of MLKL in disrupting the myelin sheath does not depend on RIP3.…”

Section: Rip1 Kinase and Mlkl Function In The Demyelination Process Amentioning

confidence: 99%

“…We showed that unlike the situation in necroptosis, during which MLKL must be activated by phosphorylation mediated by RIP3, the function of MLKL in disrupting the myelin sheath does not depend on RIP3. Specifically, mice with Mlkl, but not Rip3, knocked out showed delayed myelin sheath breakdown and reduced nerve regeneration following nerve injury (12). We therefore investigated whether MLKL may also be involved in RIPA-56's protective effects against demyelination in EAE mice.…”

Section: Rip1 Kinase and Mlkl Function In The Demyelination Process Amentioning

confidence: 99%

“…Activation markers of necroptosis such as the phosphorylated form of RIP3 and MLKL were detected in the brain of patients with MS and in the spinal cord white matter of EAE mice (8). More recently, MLKL was found to accelerate the demyelination process in a mouse sciatic nerve injury model independent of its role in necroptosis (12). This function of MLKL requires phosphorylation of MLKL at the serine 441 (mouse origin) site by an unknown kinase activated in Schwann cells after nerve injury.…”

mentioning

confidence: 99%

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RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation

Zhang

Ying

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Demyelination in the central nervous system (CNS) underlies many human diseases, including multiple sclerosis (MS). We report here the findings of our study of the CNS demyelination process using immune-induced [experimental autoimmune encephalomyelitis (EAE)] and chemical-induced [cuprizone (CPZ)] mouse models of demyelination. We found that necroptosis, a receptor-interacting protein 3 (RIP3) kinase and its substrate mixed lineage kinase domainlike protein (MLKL)-dependent cell death program, played no role in the demyelination process, whereas the MLKL-dependent, RIP3independent function of MLKL in the demyelination process initially discovered in the peripheral nervous system in response to nerve injury, also functions in demyelination in the CNS in these models. Moreover, a receptor-interacting protein 1 (RIP1) kinase inhibitor, RIPA-56, blocked disease progression in the EAE-induced model but showed no effect in the CPZ-induced model. It does so most likely at a step of monocyte elevation downstream of T cell activation and myelin-specific antibody generation, although upstream of breakdown of the blood-brain barrier. RIP1-kinase dead knock-in mice shared a similar result as mice treated with the RIP1 inhibitor. These results indicate that RIP1 kinase inhibitor is a potential therapeutic agent for immune-mediated demyelination diseases that works by prevention of monocyte elevation, a function previously unknown for RIP1 kinase.RIP1 kinase | myelin | demyelination | multiple sclerosis | MLKL M yelin is a lipid-rich (fatty) substance formed by glial cells called oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS) that protects and nourishes neuron axons by wrapping the axons (1). Physiologically, the myelin structure speeds the transmission of electrical impulses called action potentials along myelinated axons by insulating the axon and reducing axonal membrane capacitance (2). The demyelination process occurs during nerve injury and happens in many human diseases, including, for example, in the PNS, Charcot-Marie-Tooth disease (3) and abdominal numbness brought about by diabetes (4), and in the CNS, multiple sclerosis (MS), during which the insulating covers of nerve cells in the brain and spinal cord are damaged by infiltrated immune cells, such as T cells and monocytes (5,6). Patients with MS are paralyzed gradually from the lower body to the upper body and eventually die; most of these patients are young adults ranging in age from their 20s-40s (7).The molecular mechanisms that underlie these demyelination diseases are largely unknown. A recent study indicated that preventing oligodendrocytes from necroptosis, a regulated form of necrotic cell death induced by ligands of the tumor necrosis factor (TNF) receptor family or Toll-like receptors, as well as certain viral infections, could decrease disease symptoms in MS disease models of experimental autoimmune encephalomyelitis (EAE) and a cuprizone (CPZ)-induced demyelination model (8). The TNF re...

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 71%

Section: Rip1 Kinase and Mlkl Function In The Demyelination Process Amentioning

confidence: 99%

Section: Rip1 Kinase and Mlkl Function In The Demyelination Process Amentioning

confidence: 99%

mentioning

confidence: 99%

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RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation

Zhang

Ying

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot‐Marie‐Tooth 1A

Klein

Groh

Yuan

et al. 2022

Glia

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We have previously shown that targeting endoneurial macrophages with the orally applied CSF‐1 receptor specific kinase (c‐FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot‐Marie‐Tooth (CMT) 1X and 1B disease, which are genetically‐mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22‐overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re‐approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof‐of‐principle experiment, we genetically inactivated colony‐stimulating factor‐1 (CSF‐1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage‐mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.

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Necroptosis and Its Involvement in Various Diseases

Nakano

2024

Advances in Experimental Medicine and Biology

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Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve Injury

Cited by 73 publications

References 41 publications

RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation

RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation

Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot‐Marie‐Tooth 1A

Necroptosis and Its Involvement in Various Diseases

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