Trends in Molecular Medicine
ReviewInflammasomes and Cell Death: Common Pathways in Microparticle Diseases
Section snippets
Diverse Microparticles are Involved in a Large Array of Diseases
The term particle disease was coined in 1994 to describe the idea that particles generated from bone cement, metal, or polyethylene, might generate macrophage-driven inflammatory responses, periprosthetic osteolysis, and prosthetic loosening. However, deposits of crystals, misfolded proteins, functional protein aggregates, and particulate matter from airborne, occupational, or environmental sources in human tissue can cause a wide variety of pathological conditions (Table 1). As the particles
NLRP3 Inflammasome-Driven IL-1β Activation
The discovery of the cytosolic inflammasome protein complexes [15] mediating caspase-1-induced IL-1β and IL-18 activation, provided us with important insights into how cells detect and respond to cellular danger, be it of environmental, cellular, or microbial origin. This was paradigm shifting because it revealed the first mechanism for how inflammatory caspases come to be activated by danger molecules to trigger immune responses, and paved the way for the discovery of the numerous inflammasome
Distinct Mechanisms of Microparticle-Induced NLRP3 Activation
Members of the NLR family (NLRP1, NLRP3, and NLRC4), as well as the DNA-binding HIN-200 family member AIM2, and bacterium-sensing pyrin have been shown to nucleate inflammasome formation. Upon activation by their specific ligands or cellular stressors, the inflammasome sensor proteins bind to pro-caspase-1, either directly via a caspase activation and recruitment domain (CARD), or as is the case for NLRP3, indirectly via pyrin-domain interactions with the adaptor protein apoptosis-associated
Mechanisms of Microparticle-Induced Cell Death
Microparticles have traditionally been associated with a necrotic-like cell death. Necrosis can contribute to inflammatory responses through the release of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA, heat shock proteins (HSPs), histones, ATP, IL-33, IL-1α, and high-mobility group box (HMGB)1. Indeed, several of these DAMPs have been associated with damaging microparticle-induced inflammatory responses. For example, rheumatic disease has been linked to HMGB1 [44],
Treatments Targeting NLRP3 and IL-1β
Activation of IL-1β by microparticles led to the evaluation of anti-IL-1 biologics in related conditions. These agents include recombinant IL-1 receptor antagonist (IL-1Ra; anakinra), a fusion protein incorporating IL-1R and IL-1Ra (rilonacept), and a humanized monoclonal antibody against IL-1β (canakinumab). Below, we provide details of specific microparticle diseases and highlight whether targeting IL-1 has been tested and proven to be clinically beneficial, or where microparticle
Concluding Remarks
Substantial preclinical and clinical evidence now supports the idea that targeting NLRP3, caspase-1, and/or IL-1 can benefit a diverse range of conditions linked to the accumulation of damaging microparticles. However, even where evidence for the therapeutic efficacy of anti-IL-1 targeting is compelling, the route of administration (i.e., injection) and the increased risk of infection from targeting IL-1β directly, may limit widespread uptake. In this regard, the development of orally available
Acknowledgments
J.E.V. is supported by National Health and Medical Research Council of Australia Project Grants (1145788 and 1101405), an Ideas Grant (1183070). and Fellowship (1141466). M.R. is supported by a Mathison Centenary Fellowship, The University of Melbourne. I.P.W. is supported by the Reid Charitable Trusts, a Program Grant from the National Health and Medical Research Council (NHMRC) of Australia (1113577) and an NHMRC Medical Research Future Fund Practitioner Fellowship (1154325). This work was
Glossary
- Apoptosis
- caspase-dependent programmed cell death that is important for mammalian development, the prevention of cancer, and limiting pathogen infections. The two apoptotic pathways are death receptor (extrinsic) apoptosis and mitochondrial Bax/Bak-dependent (intrinsic) apoptosis. Both pathways activate the effector caspases, caspase-3, -6, and -7, which dismantle the dying cell in a manner to limit its immunogenic potential.
- Caspases
- a family of cytosolic cysteinyl aspartate-specific proteases
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