NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

Hull, Claire; Dekeryte, Ruta; Buchanan, Heather; Kamli-Salino, Sarah; Robertson, Avril A. B.; Delibegović, Mirela; Platt, Bettina

doi:10.1016/j.neuropharm.2020.108305

Cited by 23 publications

(15 citation statements)

References 62 publications

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“…MCC950, a specific inhibitor of NLRP3 inflammasome activation [ 60 ], has been recently used as a treatment for various NLRP3-related pathological models, including frontotemporal dementia [ 61 ], age-related metabolic syndrome [ 62 ], and obesity-induced insulin resistance [ 23 , 61 ]. Intraperitoneal administration of MCC950 improves glucose tolerance [ 23 , 62 , 63 ], insulin effects [ 61 , 63 ], and the insulin signaling response in skeletal muscle tissue [ 61 ]. Insulin-induced GLUT4 translocation is a critical step in this process [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our results showed, for the first time, that MCC950 increases insulin-induced GLUT4 translocation in isolated skeletal muscle fibers from HFD mice. Previous reports have shown that MCC950 treatment improves insulin sensitivity and reduces circulating plasma insulin levels [ 61 , 65 ]. Considering that the model of isolated muscle fibers excludes the influence of other cells, these results suggest that, during IR, the activation of the NLRP3 inflammasome expressed within the skeletal muscle may disrupt the insulin response through an autocrine or paracrine action of the cytokines involved (possibly through IL-1β).…”

Section: Discussionmentioning

confidence: 99%

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Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance

Américo-Da-Silva

Aguilera

Quinteros-Waltemath

et al. 2021

IJMS

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Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1β were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1β in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1β secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance

Américo-Da-Silva

Aguilera

Quinteros-Waltemath

et al. 2021

IJMS

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“…However, the effect of NLRP3 inhibition has been evaluated mainly in basal conditions, and its effect in an insulinstimulated context remains poorly explored. Additionally, in an animal model of dementia (PLB2 TAU ), glucose homeostasis is altered, displaying inflammation and glucose intolerance [131]. The pharmacological inhibition of NLRP3 improved glycemia management in PLB2 TAU animals, with an increment in InsR (Tyr1162/1163) phosphorylation, increased IRS1 protein levels and reduced JNK phosphorylation levels in the skeletal muscle and liver, showing that NLRP3 could have an active role in the metabolic signaling of insulin target organs [131].…”

Section: Nlrp3 Role In Metabolic Disorders: Limited Information In Skeletal Musclementioning

confidence: 99%

“…Additionally, in an animal model of dementia (PLB2 TAU ), glucose homeostasis is altered, displaying inflammation and glucose intolerance [131]. The pharmacological inhibition of NLRP3 improved glycemia management in PLB2 TAU animals, with an increment in InsR (Tyr1162/1163) phosphorylation, increased IRS1 protein levels and reduced JNK phosphorylation levels in the skeletal muscle and liver, showing that NLRP3 could have an active role in the metabolic signaling of insulin target organs [131]. All these data suggest a link between NLRP3 inflammasome and insulin signaling; however, relevant aspects of this NLRP3 metabolic role such as its influence over glucose uptake and GLUT4 translocation have not been studied in skeletal muscle.…”

Section: Nlrp3 Role In Metabolic Disorders: Limited Information In Skeletal Musclementioning

confidence: 99%

NLRP3 Inflammasome: Potential Role in Obesity Related Low-Grade Inflammation and Insulin Resistance in Skeletal Muscle

Jorquera

Russell

Monsalves-Álvarez

et al. 2021

IJMS

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Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.

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“…Particularly relevant here are immunoreactive Iba-1 (Ionized calcium binding adaptor molecule 1) and GFAP (Glial Fibrillary Acidic Protein) as markers for activated microglia and astrocytes respectively, which occur in close proximity to A deposits [18][19][20]. NLRP3, on the other hand, has shown promise as an experimental therapeutic target [21,22]. Similarly, protein aggregation in AD may be associated with the chronic unfolded protein response, typical for prolonged stress resulting in apoptosis and synaptic loss [15,23].…”

Section: Introductionmentioning

confidence: 99%

Sex differences in behaviour and molecular pathology in the 5XFAD model

Sil

Erfani

Lamb

et al. 2021

Preprint

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Background: The prevalence of Alzheimers Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wild-type littermate controls, to compared both sex- and genotype-dependent differences. Methods: A novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting. Results: Female 5XFAD mice had higher levels of human APP and beta-amyloid (Aβ) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.

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NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

Cited by 23 publications

References 62 publications

Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance

Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance

NLRP3 Inflammasome: Potential Role in Obesity Related Low-Grade Inflammation and Insulin Resistance in Skeletal Muscle

Sex differences in behaviour and molecular pathology in the 5XFAD model

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