Rebecca Coll

The University of Queensland | UQ · Institute for Molecular Bioscience

Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have d...

Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfam...

Background Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. Methods Bas...

How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages de...

The production of active interleukin-1 (IL-1) is a major outcome of inflammasome signaling causing local and systemic inflammation. IL-1-mediated inflammation contributes to the pathogenesis of many human diseases including autoinflammatory diseases, rheumatic diseases, and cancer. Several therapeutic strategies to block IL-1 using biologics have b...

The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases and is an exciting drug target. Here, we review the molecular basis of NLRP3 inhibition by drug-like small molecules under development as novel ther...

The non-canonical inflammasome is a signaling platform that allows for the detection of cytoplasmic lipopolysaccharides (LPS) in immune and non-immune cells. Upon detection of LPS, this inflammasome activates the signaling proteases caspase-4 and -5 (in humans) and caspase-11 (in mice). Inflammatory caspases activation leads to caspase self-process...

Inflammasomes are protein complexes in the innate immune system that regulate the production of pro-inflammatory cytokines and inflammatory cell death. Inflammasome activation and subsequent cell death often occur within minutes to an hour, so the pathway must be dynamically controlled to prevent excessive inflammation and the development of inflam...

How the danger sensor NLRP3 is activated is intensively debated. Using cryo-electron microscopy (EM) approaches, Andreeva and colleagues made the remarkable discovery that inactive NLRP3 forms a double ring of 12–16 monomers that shield its pyrin domains from the cytosol. We discuss this surprising new mechanism of inflammasome regulation.

The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is an immunological sensor that detects a wide range of microbial‐ and host‐derived signals. Inflammasome activation results in the release of the potent pro‐inflammatory cytokines IL‐1β and IL‐18 and triggers a form of inflammatory cell death known as pyroptosis. Excessive...

The NLRP3 inhibitor MCC950/CRID3 ameliorates a remarkable number of inflammatory disorders in animal models. Herein we describe a trifluoromethyl phenyl diazirine (TPD) photoaffinity probe, called TPD-950-Br, to probe the molecular interactions of MCC950. We show that TPD-950-Br covalently captures proximal species upon photo-activation and inhibit...

Signalling by innate immune cells is critical to shaping the adaptive immune response to microbial infection. In this issue of The EMBO Journal, Labzin et al reveal that the adaptive immune system can instruct the innate response to adenovirus infection. In human macrophages, antibody-coated adenovirus triggers a novel TRIM21-dependent pathway that...

Inflammasomes are signalling hubs that assemble in response to cell stress or microbial infection, and provide an activation platform for the zymogen protease, caspase-1. Upon activation, caspase-1 triggers the maturation and secretion of potent pro-inflammatory mediators (interleukin-1beta and -18) and induces cell lysis, culminating in the activa...

Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, ther...

The NOD-like receptor protein NLRC3 attenuates myeloid cell inflammatory responses. In this issue of Immunity, Uchimura et al. (2018) reveal additional T-cell-intrinsic functions for NLRC3 in restricting T cell metabolism, T helper 1 and T helper 17 cell responses, and antiviral and autoimmune responses.

In the initial published version of this article, there was a mistake in the title. The correct title should be “Mitochondrial DNA synthesis fuels NLRP3 activation”. This correction does not affect the description of the results or the conclusions of this work.

Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-...

Objectives: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatme...

Significance Toll-like receptor (TLR) signaling pathways are targeted to limit inflammation in immune cells. TLRs use adaptor proteins to drive inflammatory signaling platforms for effective microbial clearance. Here we show that MyD88 adaptor-like (MAL), an adaptor protein in TLR signaling, undergoes glutathionylation in response to LPS, driving m...

Insulin secretory sulfonylureas are widely used, cost-effective treatments for type 2 diabetes (T2D). However pancreatic β-cells are continually depleted as T2D progresses thereby rendering the sulfonylurea drug class ineffective in controlling blood glucose. Dysregulation of the innate immune system via activation of the NLRP3 inflammasome has bee...

The NLRP3 inflammasome is a multiprotein complex that regulates the activation of caspase-1 leading to the maturation of the pro-inflammatory cytokines IL-1β and IL-18, and promoting pyroptosis. Classically, the NLRP3 inflammasome in murine macrophages is activated by the recognition of pathogen-associated molecular patterns and by many structurall...

Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overex...

Innate immune crosstalk in T cells The classical view of immune activation is that innate immune cells, such as macrophages and dendritic cells, recognize invading microbes and then alert adaptive immune cells, such as T cells, to respond. Arbore et al. now show that innate and adaptive immunity converge in human and mouse T cells. Activated T cell...

The NLRP3 inflammasome is a key component of the innate immune system that induces pro-inflammatory cytokine production and cell death. Although NLRP3 is activated by many pathogens, it only appears to be critical for host defense for a limited number of specific infections. NLRP3 is however strongly associated with the initiation and pathology of...

Inflammation is the host response to microbial infection or sterile injury that aims to eliminate the insult, repair the tissue and restore homeostasis. Macrophages and the NLRP3 inflammasome are key sentinels for both types of insult. Although it is well established that the NLRP3 inflammasome is activated by microbial products and molecules relea...

The NLRP3 inflammasome controls IL-1β maturation in antigen presenting cells but a direct role for NLRP3 in human adaptive immune cells has not been described. Here we show that the NLRP3 inflammasome assembles in human CD4+ T cells and initiates caspase-1- dependent IL-1β secretion, thereby promoting IFN-γ production and Th1 differentiation in an...

The present invention provides for certain sulfonylureas and related compounds which have advantageous properties and show useful activity in the inhibition of activation of the NLRP3 inflammasome. Such compounds are useful in the treatment of a wide range of disorders in which the inflammation process, or more specifically the NLRP3 inflammasome,...

Background The NLRP3 inflammasome is a multi-protein complex activated in response to environmental pathogens. These pathogens activate toll-like receptors, initiating a cascade leading to the activation of this inflammasome resulting in caspase-1-dependant cleavage of pro-IL-1β and IL-18 to their active and mature form. Recent studies have implica...

Macrophages mediate innate immune responses that recognise foreign pathogens, and bacterial lipopolysaccharide (LPS) recruits a signalling pathway through Toll-like receptor 4 (TLR4) to induce pro-inflammatory cytokines and reactive oxygen species (ROS). LPS activation also skews the metabolism of macrophages towards a glycolytic phenotype. Here, w...

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 athero...

Background/Objectives The NLRP3 inflammasome is a multi-protein complex activated in response to environmental pathogens. These pathogens activate toll-like receptors, initiating a cascade leading to the activation of this inflammasome which results in caspase-1-dependant cleavage of pro-IL-1β and IL-18 to their active and mature form. Recent studi...

Saturated fatty acid (SFA) high-fat diets (HFD) enhance IL-1β mediated adipose inflammation and insulin resistance. However the mechanisms by which different fatty acids regulate IL-1β and subsequent effects on adipose tissue biology and insulin sensitivity in vivo remain elusive. We hypothesized that replacement of SFA for monounsaturated fatty ac...

NLRP3 is a critical component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes and complex diseases such as multiple sclerosis, type II diabetes and atherosclerosis. There is a compelling rationale to develop a potent, selective inhibitor of NLRP3. We de...

IntroductionActivation of the inflammasome has been implicated in the pathology of various auto-inflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin...

Bacterial lipopolysaccharide (LPS) stimulation of macrophages and inflammation via the Toll-like receptor 4 (TLR4) signalling pathway through NFκΒ generates reactive oxygen species (ROS) and pro-inflammatory cytokines such as IL-1β, IL-6 and TNFα. Since GSTO1-1 can catalyze redox reactions such as the deglutathionylation of proteins and has also be...

Members of the nucleotide-binding oligomerization domain receptor (NOD)-like receptor (NLR) family are implicated in the pathology of various auto-inflammatory and autoimmune diseases. While the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, has been linked to arthritis progression, little is known about its synovial regu...

The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1β. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1β. Further work identified...

Interleukin 1β (IL-1β) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-media...

The activation of Toll-Like receptors (TLRs) and Nod-like receptors (NLRs) triggers intracellular signalling pathways that lead to effector mechanisms in innate immunity and inflammation. The negative regulation of TLR signalling has been extensively studied. Current areas of research include post-transcriptional regulation by miRNA, post-translati...