Inflammasome signalling in brain function and neurodegenerative disease

Abstract

The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression.

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Fig. 1: Inflammasome activation in microglia.
Fig. 2: NLRP3 transcriptional and post-transcriptional activation.
Fig. 3: Microglia in the healthy and ageing brain.

Change history

  • 11 February 2019

    In the originally published version of this article, the competing interests statement indicated that the authors had no competing interests; however, this statement was incorrect. The statement should have read as follows: ‘M.H. receives a consultation fee from IFM Therapeutics, LLC for consultations regarding the pathogenesis and interventional strategies of neurodegenerative disease. E.L. is a scientific co-founder and consultant to IFM Therapeutics. R.M.M. declares no competing interests.’ This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

M.T.H. is supported by grants from the Deutsche Forschungsgesellschaft (DFG; DFG SFBs 1089, HE). E.L. is supported by grants from the DFG (DFG SFBs 645, 670 and 1123; TRRs 83 and 57), a grant from the US National Institutes of Health (1R01HL112661) and by a European Research Council Consolidator grant (InflammAct). E.L. and M.T.H. are members of the excellence cluster ImmunoSensation funded by the DFG. M.T.H. is supported by the European Union Joint Programme–Neurodegenerative Disease (JPND) consortium InCure (funding code 01ED1505A).

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Nature Reviews Neuroscience thanks A. LeBlanc, J. Bajramovic and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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M.T.H., R.M.M. and E.L. researched data for the article, made substantial contribution to discussion of content and contributed to the writing, review and editing of the manuscript before submission.

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Correspondence to Michael T. Heneka.

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M.H. receives a consultation fee from IFM Therapeutics, LLC for consultations regarding the pathogenesis and interventional strategies of neurodegenerative disease. E.L. is a scientific co-founder and consultant to IFM Therapeutics. R.M.M. declares no competing interests.

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Glossary

Innate immune system

Evolutionarily conserved arm of the immune system that recognizes pathogens and molecules arising in danger situations via germline-encoded signalling receptors and provides the first line of defence.

Adaptive immune system

The vertebrates’ immune subsystem that relies on clonal expansion of specialized immune cells in which highly specific receptors towards antigens are created through genetic recombination of antigen receptor gene segments to provide long-lasting acquired immunity.

T lymphocytes

A type of lymphocyte with cytotoxic, helper, regulatory and memory functions characterized by expression of the T cell receptor.

B lymphocytes

A type of lymphocyte that expresses the B cell receptor that recognizes specific antigens leading to the production of antibodies that function in providing humoral immunity.

Cell-autonomous immunity

The cell intrinsic immune defence that is provided by the function of innate immune signalling receptors expressed in the individual cell.

Inflammasome

Inflammasomes are multiprotein complexes, formed of an inflammasome sensor molecule with the adaptor ASC and the effector caspase 1, that mediate proteolytic activation of IL-1β family cytokines and pyroptotic cell death.

Pyroptosis

An inflammatory form of programmed cell death that is triggered by inflammatory caspases after activation of inflammasomes or cytoplasmic recognition of LPS and danger-associated molecules.

Sterile tissue inflammation

Inflammation induced by a variety of insults such as molecules released from dying cells that may be injured owing to trauma or crystal deposition or in chronic conditions.

Pericontusional

The area of tissue surrounding a contusion or an injury in the brain, often caused by trauma or an impact to the head.

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Heneka, M.T., McManus, R.M. & Latz, E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19, 610–621 (2018). https://doi.org/10.1038/s41583-018-0055-7

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