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The role of NLRP3 and NLRP12 inflammasomes in glioblastoma

Genes & Immunity volume 25, pages 541–551 (2024)Cite this article

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Abstract

Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

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Fig. 1: Trends of GBM occurrence rate and mean age in India.
Fig. 2: Role of inflammation in glioblastoma tumor microenvironment.
Fig. 3: Mechanism of NLRP3 activation and inflammasome formation.
Fig. 4: Mechanism of NLRP12 activation and mode of action.

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Acknowledgements

We would like to acknowledge Durgesh Meena for proofreading the manuscript.

Funding

The Inflammation Immunity and Tumor Biology Lab is supported by the Indian Institute of Technology Jodhpur, and SR is supported by the Ministry of Human Resource and Development funded GATE fellowships for pursuing a PhD.

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  1. Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India

    Sushmita Rajkhowa & Sushmita Jha

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  1. Sushmita Rajkhowa
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  2. Sushmita Jha
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SR wrote the manuscript after a literature study with inputs from SJ. The table data are compiled by SR, and the figures are created by SR using biorender.com upon the supervision of SJ.

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Correspondence to Sushmita Jha.

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Rajkhowa, S., Jha, S. The role of NLRP3 and NLRP12 inflammasomes in glioblastoma. Genes Immun 25, 541–551 (2024). https://doi.org/10.1038/s41435-024-00309-z

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