CANE, a Component of the NLRP3 Inflammasome, Promotes Inflammasome Activation.

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood.

Intestinal edema induced by LPS-induced endotoxemia is associated with an inflammasome adaptor ASC.

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1β axis, also known as the inflammasome pathway, is indispensable for IL-1β activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia.

Inflammasome assembly is required for intracellular formation of β2-microglobulin amyloid fibrils, leading to IL-1β secretion.

Introduction: Dialysis-related amyloidosis (DRA) caused by β2-microgloblin (B2M) fibrils is a serious complication for patients with kidney failure on long-term dialysis. Deposition of B2M amyloid fibrils is thought to be due not only to serum extracellular B2M but also to infiltrating inflammatory cells, which may have an important role in B2M amyloid deposition in osteoarticular tissues in patients with DRA. Here, we asked whether B2M amyloid fibrils activate the inflammasome and contribute to formation and deposition of amyloid fibrils in cells.

Molecular biology of autoinflammatory diseases.

The long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses.

Insulin amyloid fibrils interact directly with the NLRP3, resulting in inflammasome activation and pyroptotic cell death.

Introduction: Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), an intracellular pattern recognition receptor, recognizes various pathogen-associated molecular pattern and/or damage-associated molecular pattern molecules to constitute inflammasome that act as an interleukin (IL)-1β processing platform. Injected insulin is reported to induce focal amyloidosis and the formation of subcutaneous lumps called insulin balls, but the formation of subcutaneous lumps and the underlying cytotoxic mechanism has not been elucidated.

Methods: Amyloid formation was evaluated by thioflavin T spectroscopic assay and scanning electron microscopy.

A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins.

Human death domain superfamily proteins (DDSPs) play important roles in many signaling pathways involved in cell death and inflammation. Disruption or constitutive activation of these DDSP interactions due to inherited gene mutations is closely related to immunodeficiency and/or autoinflammatory diseases; however, responsible gene mutations have not been found in phenotypical diagnosis of these diseases. In this study, we comprehensively investigated the interactions of death-fold domains to explore the signaling network mediated by human DDSPs.

KN3014, a piperidine-containing small compound, inhibits auto-secretion of IL-1β from PBMCs in a patient with Muckle-Wells syndrome.

NLRP3, an intracellular pattern recognition receptor, recognizes numerous pathogens and/or its own damage-associated molecules, and forms complexes with the adaptor protein ASC. These complexes constitute the NLRP3 inflammasome, a platform for processing interleukin (IL)-1β and/or IL-18. Several NLRP3 mutations result in constitutive activation of the NLRP3 inflammasome, causing cryopyrin-associated periodic syndrome (CAPS).

The role of interleukin-1 in general pathology.

Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.

Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system.

Background: Alzheimer's disease is a neurodegenerative disease characterized by the interstitial deposition of amyloid β (Aβ) plaque, which is thought to be related to chronic neuroinflammation. Aβ is known to make fibrils via oligomers from monomers. Aβ has been reported to activate the NLRP3 inflammasome in infiltrated macrophages.

IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1β in β-cells of Langerhans' islets, directly initiates NLRP3 inflammasome activation.

Recent findings revealed that type 2 diabetes mellitus (T2D) is a chronic inflammatory disease and an islet amyloid polypeptide (IAPP)/amylin, is deposited within pancreatic islets. IAPP/amylin has been reported to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been shown to recognize pathogens and/or metabolites and complexes with the adopter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC to form a huge complex, called an inflammasome, an interleukin (IL)-1β-processing platform.

Applications of reconstituted inflammasomes in a cell-free system to drug discovery and elucidation of the pathogenesis of autoinflammatory diseases.

The inflammasome, typically consisting of a Nod-like receptor, apoptosis-associated speck-like protein, and pro-caspase-1, has recently been identified as a huge intracellular complex, which plays a crucial role in interleukin-1 maturation or specific physiological functions. Two Nod-like receptors, such as nucleotide-binding oligomerization domains-containing protein (Nod)1 and Nod2, interact with the receptor-interacting protein serine-threonine kinase (RIPK)2 accompanied by Iκ-B kinase (IKK) complexes to construct the nodosome, leading to nuclear factor (NF)-κB activation. The aberrant activation of inflammasomes or nodosomes causes autoinflammatory diseases.

Early diagnosis of early-onset sarcoidosis: a case report with functional analysis and review of the literature.

This study examined the pathogenesis of early-onset sarcoidosis (EOS) in a patient with a rare NOD2 mutation and surveyed the literature to identify the hallmark features for early diagnosis. An infant girl suffering from prolonged fever and skin rash of multiple pinkish papules and subsequent erythema nodosum was referred to our institution. Skin biopsy and DNA sequencing were performed along with cytokine profiling of the patient's serum and stimulated mononuclear cells.

Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis.

Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system.

Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease.

Objective: Although Behçet's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD.

Methods: 6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed.

IL-1 as a target in inflammation.

Inflammation is a protective response to eliminate cytotoxic agents and pathogens. Various factors are thought to be involved in the pathological changes in tissues caused by inflammation. Interleukin 1, an inflammatory cytokine, is thought to have diverse physiological functions and to play an important role in inflammatory disease.

Reconstituted AIM2 inflammasome in cell-free system.

Absent in melanoma 2 (AIM2) is an intracellular pattern-recognition receptor, which is a member of the PYHIN protein family, consisting of a PYD domain and an IFN-inducible nuclear localization (HIN) domain. AIM2 is reported to oligomerize with adaptor protein ASC upon sensing bacterial and viral cytosolic DNA in order to form the AIM2 inflammasome, which activates caspase-1 leading to IL-1β secretion. Dysregulation of AIM2 inflammasome is supposed to result in autoinflammatory and autoimmune diseases.

IL-1 as a target in inflammation.

Inflammation is a protective response to eliminate cytotoxic agents and pathogens. Various factors are thought to be involved in the pathological changes in tissues caused by inflammation. Interleukin 1, an inflammatory cytokine, is thought to have diverse physiological functions and to play an important role in inflammatory disease.