The role of inflammasomes in kidney disease

Abstract

Inflammasomes are multiprotein innate immune complexes that regulate caspase-dependent inflammation and cell death. Pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and absent in melanoma 2 (AIM2)-like receptors, sense danger signals or cellular events to activate canonical inflammasomes, resulting in caspase 1 activation, pyroptosis and the secretion of IL-1β and IL-18. Non-canonical inflammasomes can be activated by intracellular lipopolysaccharides, toxins and some cell signalling pathways. These inflammasomes regulate the activation of alternative caspases (caspase 4, caspase 5, caspase 11 and caspase 8) that lead to pyroptosis, apoptosis and the regulation of other cellular pathways. Many inflammasome-related genes and proteins have been implicated in animal models of kidney disease. In particular, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to contribute to a wide range of acute and chronic microbial and non-microbial kidney diseases via canonical and non-canonical mechanisms that regulate inflammation, pyroptosis, apoptosis and fibrosis. In patients with chronic kidney disease, immunomodulation therapies targeting IL-1β such as canakinumab have been shown to prevent cardiovascular events. Moreover, findings in experimental models of kidney disease suggest that small-molecule inhibitors targeting NLRP3 and other inflammasome components are promising therapeutic agents.

Key points

  • Canonical inflammasomes are multiprotein complexes that consist of pattern recognition receptors (PRRs), the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and caspase 1.

  • Canonical inflammasomes regulate activation of caspase 1, which results in the maturation and secretion of cytokines such as IL-1β and IL-18 and the cleavage of gasdermin D (GSDMD), which drives pyroptosis.

  • Non-canonical inflammasomes activate alternative caspases such as caspase 8, caspase 4, caspase 5 and caspase 11, which drive cell death and regulate canonical inflammasome complex assembly.

  • The NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome is activated by danger-associated molecular patterns including extracellular ATP; the absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA.

  • Inflammasome-forming PRRs and related proteins have been implicated in a variety of kidney diseases, including acute kidney injury, chronic kidney disease and diabetic kidney disease, via canonical and non-canonical pathways.

  • Novel inflammasome-targeting agents, including an IL-1β monoclonal antibody, caspase 1 inhibitors and NLRP3 inhibitors, have shown promising effects in experimental models and may provide new therapeutic strategies for kidney disease.

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Fig. 1: Inflammasome-forming genes.
Fig. 2: Activation and functions of canonical inflammasomes.
Fig. 3: The interaction between inflammasomes and pyroptosis.
Fig. 4: Activation and functions of non-canonical inflammasomes.
Fig. 5: Therapeutic strategies that block inflammasomes and their downstream effects.

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Acknowledgements

The authors’ work was supported by operating grants from the Canadian Institutes for Health Research (CIHR) and the Kidney Foundation of Canada and by a team grant under the CIHR Inflammation in Chronic Disease Signature Initiative. D.A.M. holds a Tier II Canada Research Chair. T.K. was supported by a fellowship from the Manpei Suzuki Diabetes Foundation, Japan. The authors thank J. Chun (University of Calgary) for critical review of the manuscript before submission.

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Nature Reviews Nephrology thanks B. Isermann, D. Mattson, A. Zhang and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors researched the data, discussed the content, wrote the text and reviewed or edited the manuscript before submission.

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Correspondence to Daniel A. Muruve.

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Supplementary Information

Glossary

Pathogen-associated molecular patterns

(PAMPs). Molecular structures produced by pathogens and recognized as foreign to trigger innate immune responses.

Danger-associated molecular patterns

(DAMPs). Endogenous molecules released by damaged or necrotic cells and recognized as a ‘danger’ signal to trigger innate immune responses.

Pyroptosis

A type of regulated cell death that depends on the formation of plasma membrane pores by gasdermin D. This process often occurs as a consequence of activation of inflammatory caspases such as caspase 1, caspase 4, caspase 5 and caspase 11.

Post-apoptotic secondary necrosis

The process of cell membrane degradation with the release of cell components following apoptotic cell death.

Secondary pyroptosis

A gasdermin-D-independent lytic form of cell death with a feature of pyroptosis such as IL-1β-release.

TH2 cells

T helper 2 (TH2) cells are a subset of CD4+ effector T lymphocytes that produce cytokines such as IL-4, IL-5, IL-6, IL-9, IL-13 and IL-25. TH2 cells are critical for immune responses against parasites and trigger allergic inflammation in diseases such as asthma.

Ketone body

An endogenous product of fatty acid oxidation, which occurs in the liver when carbohydrates are scarce. The three ketone bodies are acetoacetates, β-hydroxybutyrate and acetone.

Type II apoptotic cells

In type II apoptotic cells, caspase 8 activation at the death-inducing signalling complex is inhibited by the caspase 3 inhibitor X-linked inhibitor of apoptosis and cellular FLICE inhibitory protein (cFLIP). Type II cells require the mitochondrial pathway to fully initiate the cell death programme via caspase 8 activation at the outer mitochondrial membrane.

Type I apoptotic cells

Type I apoptotic cells activate caspase 8 directly via recruitment to the death-inducing signalling complex at the plasma membrane. This complex acts directly on the executioner caspase 3 to initiate apoptosis.

High-sensitivity C-reactive protein

(hsCRP). An acute phase protein that is released from the liver during bacterial infection, tissue inflammation and trauma.

Honeybee propolis

A natural resinous mixture produced by honeybees from materials collected from plants.

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Komada, T., Muruve, D.A. The role of inflammasomes in kidney disease. Nat Rev Nephrol 15, 501–520 (2019). https://doi.org/10.1038/s41581-019-0158-z

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