Dieckol Attenuated Glucocorticoid-Induced Muscle Atrophy by Decreasing NLRP3 Inflammasome and Pyroptosis

Dexamethasone (Dexa), frequently used as an anti-inflammatory agent, paradoxically leads to muscle inflammation and muscle atrophy. Receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) lead to nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome formation through nuclear factor-κB (NF-κB) upregulation. NLRP3 inflammasome results in pyroptosis and is associated with the Murf-1 and atrogin-1 upregulation involved in protein degradation and muscle atrophy. The effects of Ecklonia cava extract (ECE) and dieckol (DK) on attenuating Dexa-induced muscle atrophy were evaluated by decreasing NLRP3 inflammasome formation in the muscles of Dexa-treated animals. The binding of AGE or high mobility group protein 1 to RAGE or TLR4 was increased by Dexa but significantly decreased by ECE or DK. The downstream signaling pathways of RAGE (c-Jun N-terminal kinase or p38) were increased by Dexa but decreased by ECE or DK. NF-κB, downstream of RAGE or TLR4, was increased by Dexa but decreased by ECE or DK. The NLRP3 inflammasome component (NLRP3 and apoptosis-associated speck-like), cleaved caspase -1, and cleaved gasdermin D, markers of pyroptosis, were increased by Dexa but decreased by ECE and DK. Interleukin-1β/Murf-1/atrogin-1 expression was increased by Dexa but restored by ECE or DK. The mean muscle fiber cross-sectional area and grip strength were decreased by Dexa but restored by ECE or DK. In conclusion, ECE or DK attenuated Dexa-induced muscle atrophy by decreasing NLRP3 inflammasome formation and pyroptosis.

COVID-19 infection in a patient with a systemic autoinflammatory syndrome due to an NLRC4 inflammasomopathy

The effect of autoinflammatory diseases on SARS-CoV-2 infection remains unknown. We report a case of COVID-19 in a patient with autoinflammation with infantile enterocolitis (AIFEC) with inflammatory flares due to a mutation in the inflammasome component NLRC4. This case highlights the role of immunosuppression in patients with autoinflammation with COVID-19.

GBP5 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival at time of analysis: dead or alive. The inflammasome component and guanylate-binding protein GBP5 emerged as among the most significant differences, transcriptome-wide, when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, GBP5 expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. GBP5 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

Janus Kinase Inhibition Ameliorates Cerebral Ischemic Injury and Neuroinflammation through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

BackgroundEvidence shows that inflammatory responses play multiphasic roles in stroke pathogenesis. Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, is efficacious in COVID-19 by reducing inflammation via the JAK2/STAT3 pathway. MethodsHere, we investigated whether JAK2 inhibition has neuroprotective effects against ischemic stroke (IS) in MCAO mice in vivo and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, and explored the potential molecular mechanisms. Rux was applied to MCAO mice. Immunofluorescence staining, RT-qPCR, and western blots were used to measure the expression of NLRP3 inflammation components and proinflammatory cytokines as well as JAK2/STAT3 pathway. Local STAT3 deficiency in brain tissue was established to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment obviously improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of NLRP3 inflammasome components, proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (p-STAT3) in neurons. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMBG1, IL-1β, IL-2, and IL-6 in middle cerebral artery occlusion (MCAO) model mice, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Local STAT3 deficiency decreased histone H3 and H4 acetylation on the NLRP3 promoter and the NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Finally, the effect of Rux on the NLRP3 inflammasome was further assessed in a HT22 cell OGD/R model in vitro. Rux application markedly suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in vitro the in OGD/R HT22 cell model.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting downstream proinflammatory cytokines and H3 and H4 acetylation on the NLRP3 promoter, resulting in downregulation of NLRP3 inflammasome component expression.

The inflammasome components NLRP3 and ASC act in concert with IRGM to rearrange the Golgi during HCV infection.

Hepatitis C virus (HCV) infection triggers Golgi fragmentation through the Golgi-resident protein immunity-related GTPase M (IRGM). Here, we report the role of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) and ASC (Apoptosis-associated speck-like protein containing a CARD), two inflammasome components, in the initial events leading to this fragmentation. We show that ASC resides at the Golgi with IRGM at homeostasis. Upon infection, ASC dissociates from both IRGM and Golgi and associates with HCV-induced NLRP3. NLRP3 silencing inhibits Golgi fragmentation. ASC silencing disrupts the Golgi structure in both control and infected cells and reduces the localization of IRGM at the Golgi. IRGM-depletion in the ASC silenced cells cannot totally restore the Golgi structure. These data highlight a role for ASC, upstream of the formation of the inflammasome, in regulating IRGM through its control on the Golgi. A similar mechanism occurs in response to Nigericin treatment, but not in cells infected with another member of the Flaviviridae family, Zika virus (ZIKV). We propose a model for a newly ascribed function of the inflammasome components in Golgi structural remodeling during certain stimuli. IMPORTANCE Numerous pathogens can affect cellular homeostasis and organelle dynamics. Hepatitis C virus (HCV) triggers Golgi fragmentation through the immunity-related GTPase M (IRGM), a resident Golgi protein to enhance its lipid supply for replication. Here, we reveal the role of the inflammasome components NLRP3 and ASC in this process, thus uncovering a new interplay between effectors of inflammation and viral infection or stress. We show that the inflammasome component ASC resides at the Golgi under homeostasis and associates with IRGM. Upon HCV infection, ASC is recruited to NLRP3 and dissociates from IRGM causing Golgi fragmentation. Our results uncover that aside from their known function in the inflammation response, this host defense regulators also ensure the maintenance of intact intracellular structure in homeostasis status, while their activation relieves factors leading to Golgi remodeling.

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

Cognitive symptoms are prevalent in the elderly and are associated with an elevated risk of developing dementia. Disease-driven changes can cause cognitive disabilities in memory, attention, and language. The inflammasome is an innate immune intracellular complex that has a critical role in the host defense system, in that it senses infectious pathogen-associated and endogenous danger-associated molecular patterns. An unbalanced or dysregulated inflammasome is associated with infectious, inflammatory, and neurodegenerative diseases. Due to its importance in such pathological conditions, the inflammasome is an emerging drug target for human diseases. A growing number of studies have revealed links between cognitive symptoms and the inflammasome. Several studies have shown that reducing the inflammasome component mitigates cognitive symptoms in diseased states. Therefore, understanding the inflammasome regulatory mechanisms may be required for the prevention and treatment of cognitive symptoms. The purpose of this review is to discuss the current understanding of the inflammasome and its relationships with cognitive symptoms in various human diseases.

New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation

ABSTRACTThe NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.