Inflammasomes are assembled by innate immune sensors that cells employ to detect a range of danger signals and respond with pro‐inflammatory signalling. Inflammasomes activate inflammatory caspases, which trigger a cascade of molecular events with the potential to compromise cellular integrity and release the IL‐1β and IL‐18 pro‐inflammatory cytokines. Several molecular mechanisms, working in concert, ensure that inflammasome activation is tightly regulated; these include NLRP3 post‐translational modifications, ubiquitination and phosphorylation, as well as single‐domain proteins that competitively bind to key inflammasome components, such as the CARD‐only proteins (COPs) and PYD‐only proteins (POPs). These diverse regulatory systems ensure that a suitable level of inflammation is initiated to counteract any cellular insult, while simultaneously preserving tissue architecture. When inflammasomes are aberrantly activated can drive excessive production of pro‐inflammatory cytokines and cell death, leading to tissue damage. In several autoinflammatory conditions, inflammasomes are aberrantly activated with subsequent development of clinical features that reflect the degree of underlying tissue and organ damage. Several of the resulting disease complications may be successfully controlled by anti‐inflammatory drugs and/or specific cytokine inhibitors, in addition to more recently developed small‐molecule inhibitors. In this review, we will explore the molecular processes underlying the activation of several inflammasomes and highlight their role during health and disease. We also describe the detrimental effects of these inflammasome complexes, in some pathological conditions, and review current therapeutic approaches as well as future prospective treatments.

P2X receptors are Ca²⁺-permeable cationic channels in the cell membranes, where they play an important role in mediating a diversity of physiological and pathophysiological functions of extracellular ATP. Mammalian cells express seven P2X receptor genes. Single nucleotide polymorphisms (SNPs) are widespread in the P2RX genes encoding the human P2X receptors, particularly the human P2X7 receptor. This article will provide an overview of the non-synonymous SNPs (NS-SNPs) that have been associated with or implicated in altering the susceptibility to pathologies or disease conditions, and discuss the consequences of the mutations resulting from such NS-SNPs on the receptor functions. Disease-associated NS-SNPs in the P2RX genes have been valuable in understanding the disease etiology and the receptor function, and are promising as biomarkers to be used for the diagnosis and development of stratified therapeutics.

The adverse biological impact of orthopaedic wear debris currently limits the long-term safety of human joint replacement devices. We investigated the role of particle size, surface composition and donor variation in influencing the biological impact of silicon nitride as a bioceramic for orthopaedic applications. Silicon nitride particles were compared to the other commonly used orthopaedic biomaterials (e.g. cobalt-chromium and Ti-6Al-4V alloys). A novel biological evaluation platform was developed to simultaneously evaluate cytotoxicity, inflammatory cytokine release, oxidative stress, and genotoxicity potential of particles using peripheral blood mononuclear cells (PBMNCs) from individual human donors. Irrespective of the particle size, silicon nitride did not cause any adverse responses whereas cobalt-chromium wear particles caused donor-dependent cytotoxicity, TNF-α cytokine release, oxidative stress, and DNA damage in PBMNCs after 24 h. Despite being similar in size and morphology, silicon dioxide nanoparticles caused the release of significantly higher levels of TNF-α compared to silicon nitride nanoparticles, suggesting that surface composition influences the inflammatory response in PBMNCs. Ti-6Al-4V wear particles also released significantly elevated levels of TNF-α cytokine in one of the donors. This study demonstrated that silicon nitride is an attractive orthopaedic biomaterial due to its minimal biological impact on human PBMNCs.

The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models and docked three structurally distinct inhibitors using in silico approaches and show they have a similar mode of binding in which Phe95 plays a key role by forming pi-stacking interactions. Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity. This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity. Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.