Rapamycin combined with MCC950 to treat multiple sclerosis in experimental autoimmune encephalomyelitis

Xu, Ling; Zhang, Cuili; Jiang, Nan; He, Dan; Bai, Ying; Xin, Yi

doi:10.1002/jcb.27792

Cited by 43 publications

(35 citation statements)

References 36 publications

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“…MCC950 improved allodynia threshold in a murine model of RRMS and attenuated relapses [97]. A later study investigated the value of a rapamycin-MCC950 combination and found that MCC950 enhanced the activity of rapamycin (immunosuppressant) and that this combination was effective in mitigating MS symptoms and cytokine release [98]. IC100 is the most recently developed inflammasome inhibitor and is a humanized antibody developed against the ASC component of inflammasomes, thus having the ability to inhibit several inflammasomes including NLRP1, NLRP3, NLCR4 and AIM2.…”

Section: Inflammasomes As Drug Targetsmentioning

confidence: 99%

Section: Inflammasomes As Drug Targetsmentioning

confidence: 99%

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Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan

Vaccari

Keane

2020

J Neuroinflammation

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Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), and it remains the most common immune-mediated disorder affecting the CNS. While the cause of MS is unclear, the underlying pathomechanisms are thought to be either destruction by autoimmune T cells or dysfunction of myelin-producing cells. Recent advances have indicated that inflammasomes contribute the etiology of MS. Inflammasomes are multiprotein complexes of the innate immune response involved in the processing of caspase-1, the activation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as the cell death-mediated mechanism of pyroptosis and the activation of the adaptive immune response. Here we review the literature to date on the role of different inflammasome signaling pathways in the pathogenesis of MS and how these pathways may be targeted to reduce deleterious inflammatory processes and improve outcomes in this patient population.

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Section: Inflammasomes As Drug Targetsmentioning

confidence: 99%

Section: Inflammasomes As Drug Targetsmentioning

confidence: 99%

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Govindarajan

Vaccari

Keane

2020

J Neuroinflammation

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“…On the other hand, studies in humans showed that autophagy activity is not increased in neither the peripheral nor brain-circulating CD4+ T cells of MS patients compared with controls, despite having increased Atg5 gene and protein levels [254]. Other studies centered on the role of microglia-related inflammation suggest that autophagy induction via mTOR inhibition contributes to reducing both demyelination and inflammation in EAE [255]. As far as it concerns neurodegenerative disorders, autophagy induction seems to play a beneficial effect in counteracting acute and chronic inflammation [256].…”

Section: Autophagy and Proteasome Linking Altered Immunity And Synmentioning

confidence: 99%

Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity

Limanaqi

Biagioni

Busceti

et al. 2019

IJMS

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In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.

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“…As autophagy can have both beneficial [ 257 ] and deleterious [ 258 ] effects depending on the disease context [ 252 ], we should be very cautious when interpreting the global effects of autophagy-targeting treatment because it could be cell- and time-specific. We already observed that the aberrant autophagy activity (downregulation or hyperactivation) that occurs in pathological settings is not a general feature that equally affects all organs or tissues of any individual [ 259 ].…”

Section: Therapeutic Approach To Npslementioning

confidence: 99%

From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

Bendorius

Muller

et al. 2018

IJMS

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It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood–brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.

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Rapamycin combined with MCC950 to treat multiple sclerosis in experimental autoimmune encephalomyelitis

Cited by 43 publications

References 36 publications

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity

From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

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