The inflammasomes: mechanisms of activation and function

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In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases. While defined ligands have been identified for the NLRP1, IPAF, and AIM2 inflammasomes, little is known about the activation mechanisms of the NLRP3 inflammasome. Numerous different molecular entities, such as various crystals, pore-forming toxins, or extracellular ATP can trigger the NLRP3 inflammasome. Recent work proposes that NLRP3 is activated indirectly by host factors that are generated in response to NLRP3 triggers.

Introduction

In the last decade many molecular mechanisms that operate to activate cells in response to infection and tissue damage have been discovered. Innate immune cells and other host cells express a group of transmembrane and cytosolic signaling receptors, which are triggered by molecules uniquely found in microbes or by host molecules that appear in nonphysiological locations or that are chemically altered during tissue damage. Most of the innate immune signaling receptors, such as members of the Toll-like receptor (TLR) or the Rig-I like helicase families, activate distinct transcriptional programs leading to inflammation, antiviral responses, and the induction of adaptive immunity [1]. The members of the nucleotide-binding domain leucine-rich repeat containing (NLR) and the pyrin domain and HIN200 domain containing (PYHIN) protein families can form the so-called inflammasomes, which initiate the cleavage and release of interleukin-1 family cytokines [2].

While most of the hitherto recognized inflammasomes form in response to a certain molecular trigger, the NLRP3 inflammasome can be activated by a wide variety of molecular substances of dissimilar physico-chemical nature. Here, the recent progress in our  still incomplete  understanding of the mechanisms leading to inflammasome activation is reviewed.

Section snippets

Dual control of the IL-1b cytokine family activation

Many cells can produce and secrete cytokines in response to their activation by cellular stimuli. Most cytokines are transcriptionally regulated and, upon induction, are released into the environment through the secretory pathway. The IL-1b cytokine family members are also under transcriptional control; however, these cytokines differ from other cytokines in that they lack a leader sequence and they are expressed as biologically inactive proforms in the cytoplasm of cells. These cytokine

NLR and PYHIN family proteins can form inflammasomes

The NLR proteins are commonly organized into three domains, a C-terminal leucine-rich repeat (LRR) domain, an intermediate nucleotide binding and oligomerization domain (NOD, also called NACHT domain), and a N-terminal pyrin (PYD), caspase activation and recruitment domain (CARD) or a baculovirus inhibitor of apoptosis repeat domain (BIR). The LRR domains of these proteins are hypothesized to interact with putative ligands and play a role in autoregulation of these proteins. The NACHT domain

At least two signals are required for NLRP3 inflammasome activation

Cells that are activated to assemble the NLRP3 inflammasome produce copious amounts of proinflammatory cytokines and also secrete other leaderless proteins involved in inflammation and the ensuing tissue repair [28]. Concomitantly, a special form of cell death, termed pyroptosis, is induced leading to the destruction of the activated cell and spillage of cellular contents [29]. Hence, NLRP3 inflammasome activation generates a drastic immune response with far-reaching consequences for the

Possible mechanisms of NLRP3 activation and parallels to plant immunity

The exact sequence of molecular events leading to NLRP3 inflammasome activation is currently not well understood. Recently, two  potentially interconnected  pathways upstream of NLRP3 activation have been proposed to operate. According to one hypothesis, NLRP3 activators lead to the production of reactive oxygen species (ROS), which could be sensed directly or indirectly by NLRP3 [14, 17••, 34]. Support for this hypothesis comes from experiments demonstrating that ROS scavengers, such as N-acetyl

Conclusion and future direction

In recent years it became increasingly evident that in addition to their fundamental role for the development of autoinflammatory diseases [39], inflammasomes are also critical for infection control, the recognition of tissue damage, and for the development of immune pathologies in general. Recent evidence furthermore suggests a role of NLRP3 in tumor surveillance [40]. Not surprisingly, the NLRP3 inflammasome represents an attractive drug target. While much progress toward the understanding

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Funding by the National Institutes of Health (AI-065483 and AI-083713) and the Dana Foundation is acknowledged.

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