Trends in Molecular Medicine
Volume 26, Issue 11, November 2020, Pages 1003-1020
Journal home page for Trends in Molecular Medicine

Review
Inflammasomes and Cell Death: Common Pathways in Microparticle Diseases

https://doi.org/10.1016/j.molmed.2020.06.005Get rights and content

Highlights

  • Insoluble microparticles are associated with diseases of the joint, kidney, heart, and brain.

  • Diverse microparticle types, from crystals and proteins to environmental hazards, are detected by the innate-immune NOD-like receptor protein (NLRP)3 inflammasome sensor. Distinct from other NLRP3 activators, microparticle NLRP3 signaling requires their phagocytosis and lysosomal rupture.

  • Activation of NLRP3 coincides with cell death to release IL-1β and other immunogenic molecules. Strikingly, microparticle killing may occur when known cell death programs are eliminated, including pyroptosis, apoptosis, and necroptosis.

  • Blockade of IL-1, NLRP3, or caspase-1, provides significant benefit in humans and/or animal models of microparticle-associated conditions, including atherosclerosis, gout, Alzheimer’s disease, and Parkinson’s disease.

The accumulation of cellular and environmental microparticles has been linked to many diseases associated with tissue inflammation. These particulate-driven diseases include joint, lung, kidney, cardiovascular, and neurodegenerative disorders. Recently a conserved proinflammatory inflammasome signaling pathway elicited by such microparticles has become apparent. Here, we review disease-promoting microparticles and the mechanisms by which they trigger activation of the inflammasome complexes responsible for generating bioactive interleukin-1β (IL-1β) and inducing cell death. We highlight how microparticle-induced inflammasome and cell death responses diverge from canonical inflammasome activators, and discuss the preclinical and clinical targeting of inflammasomes to treat microparticle-driven 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

References (177)

  • U. Andersson et al.

    The role of HMGB1 in the pathogenesis of rheumatic disease

    Biochim. Biophys. Acta Gene Regul. Mech.

    (2010)
  • E. Mortaz

    ATP and the pathogenesis of COPD

    Eur. J. Pharmacol.

    (2010)
  • J. Desai

    Particles of different sizes and shapes induce neutrophil necroptosis followed by the release of neutrophil extracellular trap-like chromatin

    Sci. Rep.

    (2017)
  • M. Couderc

    Efficacy of anakinra in articular chondrocalcinosis: report of three cases

    Joint Bone Spine Rev. Rhum.

    (2012)
  • J. Zhu

    Recombinant human interleukin-1 receptor antagonist treatment protects rats from myocardial ischemia–reperfusion injury

    Biomed. Pharmacother.

    (2019)
  • G. Balasubramaniam

    Improved renal function in diabetic patients with acute gout treated with anakinra

    Kidney Int.

    (2015)
  • J.Y. Yeun

    C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients

    Am. J. Kidney Dis.

    (2000)
  • J. Zimmermann

    Inflammation enhances cardiovascular risk and mortality in hemodialysis patients

    Kidney Int.

    (1999)
  • S.R. Mulay et al.

    Crystallopathies

    N. Engl. J. Med.

    (2016)
  • K.H. Maurer et al.

    Hydroxyapatite phagocytosis by human polymorphonuclear leucocytes

    Ann. Rheum. Dis.

    (1979)
  • M. Nakayama

    Macrophage recognition of crystals and nanoparticles

    Front. Immunol.

    (2018)
  • H.R. Schumacher et al.

    Sequential changes in human polymorphonuclear leukocytes after urate crystal phagocytosis. An electron microscopic study

    Arthritis Rheum. Off. J. Am. Coll. Rheumatol.

    (1971)
  • J.E. Vince et al.

    The intersection of cell death and inflammasome activation

    Cell. Mol. Life Sci.

    (2016)
  • D.J. Mccarty et al.

    Identification of urate crystals in gouty synovial fluid

    Ann. Intern. Med.

    (1961)
  • D. McCarty

    Phagocytosis of urate crystals in gouty synovial fluid

    Am. J. Med. Sci.

    (1962)
  • A. Allison

    An examination of the cytotoxic effects of silica on macrophages

    J. Exp. Med.

    (1966)
  • P. Dieppe et al.

    Crystals and Joint Disease

    (1983)
  • M.T. Shio

    Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases

    PLoS Pathog.

    (2009)
  • C. Dostert

    Malarial hemozoin is a Nalp3 inflammasome activating danger signal

    PLoS One

    (2009)
  • A. Halle

    The NALP3 inflammasome is involved in the innate immune response to amyloid-β

    Nat. Immunol.

    (2008)
  • I.-C. Stancu

    Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

    Acta Neuropathol.

    (2019)
  • P. Menu et al.

    The NLRP3 inflammasome in health and disease: the good, the bad and the ugly

    Clin. Exp. Immunol.

    (2011)
  • L.M. Booshehri et al.

    CAPS and NLRP3

    J. Clin. Immunol.

    (2019)
  • J. Chen et al.

    PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation

    Nature

    (2018)
  • Y. He

    NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux

    Nature

    (2016)
  • H. Shi

    NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component

    Nat. Immunol.

    (2016)
  • E.O. Samstad

    Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release

    J. Immunol.

    (2014)
  • F.J. Sheedy

    CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation

    Nat. Immunol.

    (2013)
  • C.R. Stewart

    CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer

    Nat. Immunol.

    (2010)
  • T.L. Flach

    Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity

    Nat. Med.

    (2011)
  • V. Hornung et al.

    lle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization

    Nat. Immunol.

    (2008)
  • P. Duewell

    NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

    Nature

    (2010)
  • G.M. Orlowski

    Multiple cathepsins promote pro–IL-1β synthesis and NLRP3-mediated IL-1β activation

    J. Immunol.

    (2015)
  • H. Lima

    Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death

    Cell Cycle

    (2013)
  • M. Rashidi

    The pyroptotic cell death effector gasdermin D is activated by gout-associated uric acid crystals but is dispensable for cell death and IL-1β release

    J. Immunol.

    (2019)
  • F. Shu

    Cholesterol crystal-mediated inflammation is driven by plasma membrane destabilization

    Front. Immunol.

    (2018)
  • N. Varsano

    Two polymorphic cholesterol monohydrate crystal structures form in macrophage culture models of atherosclerosis

    Proc. Natl. Acad. Sci.

    (2018)
  • A. So

    IL1 inhibition in gout—where are we a decade on?

    Arthritis Res. Ther.

    (2019)
  • H.M. Hoffman

    Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal–induced inflammation in mice

    Arthritis Rheum.

    (2010)
  • F. Martinon

    Gout-associated uric acid crystals activate the NALP3 inflammasome

    Nature

    (2006)
  • Cited by (35)

    • Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells

      2022, Ecotoxicology and Environmental Safety
      Citation Excerpt :

      NLRP3 is the most well-known comprehensive inflammasome. Activation of NLRP3 promotes the maturation and secretion of IL-1β and IL-18 and mediates special programmed cell deaths such as pyroptosis and necroptosis (Rashidi et al., 2020). Pyroptosis is a form of caspase-dependent inflammatory cell death, and the primary function is to induce strong inflammatory responses that defend the host against microbe infection, but excessive pyroptosis could lead to several inflammatory diseases (Burdette et al., 2021).

    • Microalgal bioactive components as antiinflammatory and antioxidant agents for health promotion

      2022, Current Advances for Development of Functional Foods Modulating Inflammation and Oxidative Stress
    • Luteolin activates Tregs to promote IL-10 expression and alleviating caspase-11-dependent pyroptosis in sepsis-induced lung injury

      2021, International Immunopharmacology
      Citation Excerpt :

      Regulated cell death (RCD) is a pattern of cell death regulated by multiple intracellular signal transduction pathways under physiological or pathological conditions. Accumulation of cellular and environmental particles is associated with many diseases related to tissue inflammation [32]. Pyroptosis and necroptosis could release intracellular damage-associated molecular patterns (DAMPs) and inflammatory mediator, thereby creates an inflammatory environment [13].

    • Pyroptosis by caspase-11 inflammasome-Gasdermin D pathway in autoimmune diseases

      2021, Pharmacological Research
      Citation Excerpt :

      Among them, canonical inflammasomes are assembled by a specific pattern recognition receptor (eg. NLRP1, NLRP3, NLRC4, AIM2 or pyrin, etc.), the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 [6]. Relatively, NLRP6 and NLRP9 are not well established as inflammasome compared with those canonical inflammasomes mentioned above.

    View all citing articles on Scopus
    View full text