Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

Corcoran, Sarah E.; Halai, Reena; Cooper, Matthew A.

doi:10.1124/pharmrev.120.000171

Cited by 98 publications

(75 citation statements)

References 245 publications

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“…Hence, targeting on inhibiting NLRP3 inflammasome and investigating potential mechanism may be a crucial and effective aspect in liver injury. MCC950 is one of the most potent and selective NLRP3 inhibitors discovered to date and it can bind directly and specifically to NLRP3, irrespective of its activation state (10). More recently, MCC950 was reported to alleviate chronic cholestatic liver injury (11), fulminant hepatitis (12), and liver fibrosis (13).…”

Section: Introductionmentioning

confidence: 99%

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

et al. 2021

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Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

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Section: Introductionmentioning

confidence: 99%

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

et al. 2021

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“…As key sensors detecting different danger signals, such as inflammatory stimuli and bacteria, the inflammasomes, and particularly the NLRP3 inflammasome, have been associated with a wide range of conditions, including IBD, Parkinson, type II diabetes, etc. [ 50 , 51 ] Preclinical models of intestinal inflammation, chronic pain and others, treated with inflammasome inhibitors have generated promising findings to pursue the next generation of inflammasome inhibitors into clinical trials [ 50 , 51 , 52 ]. Our findings add intestinal inflammatory and functional disorders with alterations in the microbiota composition, immune system, and pain to the ever-growing conditions that can be therapeutically targeted by the inflammasomes.…”

Section: Discussionmentioning

confidence: 99%

Inflammasome Signaling Regulates the Microbial–Neuroimmune Axis and Visceral Pain in Mice

Aguilera

Rossini

Hickey

et al. 2021

IJMS

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Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain–gut interactions, but their role in microbiota–neuro–immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut–neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.

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“…The effects of flufenamic acid and mefenamic acid on chloride efflux indicate that these compounds target the upstream signaling event of NLRP3 and have other unavoidable biological activities ( 33 ). A diarylsulfonylurea-containing compound termed as MCC950, is considered one of the most potent and selective inhibitor of NLRP3 inflammasome ( 34 ). But the mechanism of MCC950 on NLRP3 inflammasome is not understood.…”

Section: Discussionmentioning

confidence: 99%

Erianin: A Direct NLRP3 Inhibitor With Remarkable Anti-Inflammatory Activity

Zhang

et al. 2021

Front. Immunol.

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Erianin (Eri) is the extract of Dendrobium chrysotoxum Lindl. The NLRP3 inflammasome is a multiprotein complex that plays key roles in a wide variety of chronic inflammation-driven human diseases. Nevertheless, little is known about the protection of Eri against NLRP3 inflammasome-related diseases. In this study, we demonstrated that Eri inhibited NLRP3 inflammasome activation in vitro and in vivo. Mechanistically, Eri directly interacted with NLRP3, leading to inhibition of NLRP3 inflammasome assembly. Eri associated with the Walker A motif in the NACHT domain and suppressed NLRP3 ATPase activity. In mouse models, Eri had therapeutic effects on peritonitis, gouty arthritis and type 2 diabetes, via NLRP3. More importantly, Eri was active ex vivo for synovial fluid cells and monocytes from patients with IAV infection and gout. Eri may serve as a potential novel therapeutic compound against NLRP3-driven diseases.

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Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950

Cited by 98 publications

References 245 publications

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function

Inflammasome Signaling Regulates the Microbial–Neuroimmune Axis and Visceral Pain in Mice

Erianin: A Direct NLRP3 Inhibitor With Remarkable Anti-Inflammatory Activity

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