Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Péladeau, Christine; Sandhu, Jagdeep K.

doi:10.3390/ijms22116068

Cited by 10 publications

(7 citation statements)

References 243 publications

(291 reference statements)

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“…Similar to the NLRC4 disk structure, the NLRP3 inflammasome may be composed of 11 subunits. Subsequently, caspase-1 cleaves two inactive pro-inflammatory cytokines, pro-interleukin 1-beta (pro-IL-1β) and pro-interleukin 18 (pro-IL-18), into active forms of IL-1β and IL-18 [ 43 ].…”

Section: Types Of Inflammasomesmentioning

confidence: 99%

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Manshouri,

Seif,

Kamali

et al. 2024

Cell Commun Signal

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Inflammasomes are complex platforms for the cleavage and release of inactivated IL-1β and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1β and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.

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Section: Types Of Inflammasomesmentioning

confidence: 99%

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Manshouri,

Seif,

Kamali

et al. 2024

Cell Commun Signal

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“…Another important mediator of the inflammatory process that is over-active in neuromuscular diseases including DMD is the NLRP3 inflammasome [ 81 ]. Inflammasomes are cytosolic-receptors of the innate immune system that assemble in response to harmful stimuli, mediating the activation of caspase-1 [ 82 ] ( Figure 1 B).…”

Section: Chronic Inflammation In Skeletal Muscle Dystrophiesmentioning

confidence: 99%

Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

et al. 2022

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Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.

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“…In ALS, accumulation of aggregates drives caspase-1-mediated proteolytic cleavage and secretion of proinflammatory cytokines, that further amplify inflammatory responses, resulting in chronic inflammation, tissue damage and cell death 8 .…”

Section: Introductionmentioning

confidence: 99%

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis (RAP-ALS study)

Mandrioli

D’Amico

Zucchi

et al. 2023

Preprint

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In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells (Tregs), and autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Rapamycin has never been tested in ALS patients. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in Tregs from baseline to treatment end, was not attained. Of the secondary outcomes, rapamycin decreased mRNA relative expression of pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. Rapamycin, in combination with riluzole, was well tolerated and provided reassuring safety findings. Based on immunological effects, plasma concentration stability and safety, rapamycin 1 mg/m2/day resulted the best dosage in this study, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.

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Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Cited by 10 publications

References 243 publications

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis (RAP-ALS study)

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