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Homeostasis-altering molecular processes as mechanisms of inflammasome activation

Nature Reviews Immunology volume 17, pages 208–214 (2017)Cite this article

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Abstract

The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term 'homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.

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Figure 1: Innate immune receptors are limited by structural conservation.
Figure 2: Direct and indirect pathways of innate immune sensing.
Figure 3: Molecular basis for pyrin as a signal integrator for HAMP recognition.
Figure 4: ROS production as a HAMP that triggers innate immunity in plants and mammals.
Figure 5: Theoretical models for counter-regulatory and counter-counter-regulatory systems in the detection of HAMPs.

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Authors and Affiliations

  1. Adrian Liston is at the Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium; and at the VIB Center for Brain and Disease Research, Leuven 3000, Belgium.,

    Adrian Liston

  2. and at the VIB Center for Brain and Disease Research, Leuven 3000, Belgium.,

    Adrian Liston

  3. Seth L. Masters is at the Inflammation Division, Australia; and at the Department of Medical Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, University of Melbourne, Parkville, Victoria 3010, Australia.,

    Seth L. Masters

  4. and at the Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.,

    Seth L. Masters

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Correspondence to Adrian Liston.

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Liston, A., Masters, S. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol 17, 208–214 (2017). https://doi.org/10.1038/nri.2016.151

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