mcc-950 and Inflammation

NLRP3 (Nod-like receptor protein 3) belongs to the NOD-like receptor family, which is activated by pathogen and damage-associated signals to form a multimeric protein complex, known as the NLRP3 inflammasome. NLRP3 inflammasome activation leads to release of proinflammatory cytokines IL-1β and IL-18, thus inducing pyroptosis, a programmed cell death mechanism. Dysregulation of the NLRP3 inflammasome pathway is closely related to the development of many human diseases, such as neuroinflammation, metabolic inflammation, and immune inflammation. Emerging studies have suggested NLRP3 inflammasome as a potential drug-target for inflammatory diseases. Several small molecules have recently been identified to target the NLRP3 inflammasome pathway directly or indirectly and alleviate related disease pathology. This review summarizes recent evolving landscape of small molecule inhibitor development targeting the NLRP3 inflammasome pathway.

Topics: Humans; Inflammasomes; Inflammation; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Small Molecule Libraries; Structure-Activity Relationship

Inflammasomes are high molecular weight complexes that sense and react to injury and infection. Their activation induces caspase-1 activation and release of interleukin-1β, a pro-inflammatory cytokine involved in both acute and chronic inflammatory responses. There is increasing evidence that inflammasomes, particularly the NLRP3 inflammasome, act as guardians against noninfectious material. Inappropriate activation of the NLRP3 inflammasome contributes to the progression of many noncommunicable diseases such as gout, type II diabetes, and Alzheimer's disease. Inhibiting the inflammasome may significantly reduce damaging inflammation and is therefore regarded as a therapeutic target. Currently approved inhibitors of interleukin-1β are rilonacept, canakinumab, and anakinra. However, these proteins do not possess ideal pharmacokinetic properties and are unlikely to easily cross the blood-brain barrier. Because inflammation can contribute to neurological disorders, this review focuses on the development of small-molecule inhibitors of the NLRP3 inflammasome.

Topics: Animals; Humans; Inflammasomes; Inflammation; Molecular Conformation; Small Molecule Libraries; Structure-Activity Relationship

Topics: Caspase 1; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein

Rosacea is a chronic inflammatory skin disease characterized by immune response-dependent erythema and pustules. Although the precise etiology of rosacea remains elusive, its pathogenesis is reportedly associated with an increased level of antimicrobial peptide LL-37. However, molecular mechanisms underlying the progression of rosacea via LL-37 remain poorly understood. Here, we examined the potential role of LL-37 in rosacea-like skin inflammatory phenotypes at a molecular level. Our in vitro data demonstrated that LL-37 promotes NLRP3-mediated inflammasome activation in lipopolysaccharide-primed macrophages, indicated by the processing of caspase-1 and IL-1β. LL-37 was internalized into the cytoplasm of macrophages through P2X7 receptor-mediated endocytosis. Intracellular LL-37 triggered the assembly and activation of NLRP3-ASC inflammasome complex by facilitating lysosomal destabilization. Consistent with these in vitro results, intradermal LL-37 administration induced in vivo caspase-1 activation and ASC speck formation in the skin of Nlrp3-expressing, but not in Nlrp3-deficient, mice. Intradermal injection of LL-37 elicited profound recruitment of inflammatory Gr1

Topics: Animals; Antimicrobial Cationic Peptides; Caspase 1; Cathelicidins; Cells, Cultured; Female; Furans; Indenes; Inflammasomes; Inflammation; Interleukin-1beta; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Rosacea; Sulfonamides

The NLRP3 inflammasome plays a critical role in inflammation-mediated human diseases and represents a promising drug target for novel anti-inflammatory therapies. Hispanolone is a labdane diterpenoid isolated from the aerial parts of

Topics: Animals; Diterpenes; Humans; Inflammasomes; Inflammation; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Structure-Activity Relationship

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

Topics: Animals; Carrier Proteins; Cryopyrin-Associated Periodic Syndromes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Inflammasomes; Inflammation; Interleukin-1beta; Mice; Multiple Sclerosis; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfonamides; Sulfones