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Does caspase-12 suppress inflammasome activation?

Nature volume 534, pages E1–E4 (2016)Cite this article

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A Corrigendum to this article was published on 29 May 2013

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ARISING FROM M. Saleh et al. Nature 440, 1064–1068 (2006); doi:10.1038/nature04656 corrigendum Nature 508, 274 (2013); doi:10.1038/nature12181

Inflammasomes are cytosolic protein complexes that activate caspase-1, an inflammatory protease that converts pro-interleukin (IL)-1β and IL-18 into their secreted, bioactive forms1; and mechanisms regulating inflammasome activation have attracted interest because aberrant caspase-1 activity is implicated in diverse inflammatory and neurodegenerative diseases2. Saleh et al.3,4 reported that caspase-12 acts as a dominant-negative regulator of caspase-1 activation and that caspase-12 deletion in splenocytes enhanced secretion of IL-1β and IL-18. We sought to confirm and further explore the role of caspase-12 in inflammasome inhibition, however, analysis of three independently generated caspase-12−/− mouse strains has brought into question the notion that caspase-12 is a physiologic inhibitor of caspase-1 activation. In contrast to the findings of Saleh et al.3,4, we further show that reported caspase-12-deficient mice also lack caspase-11 expression, and this prevented non-canonical caspase-1 activation.

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Figure 1: Canonical caspase-1 activation is not increased in reported caspase-12−/−S mice, and defective caspase-11 expression prevents non-canonical caspase-1 activation.
Figure 2: Caspase-12 deletion does not increase caspase-1-dependent cytokine secretion in BMDMs and in in vivo challenged caspase-12−/−V mice.

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Author notes

  1. Lieselotte Vande Walle and Daniel Jiménez Fernández: These authors contributed equally to this work.

Authors and Affiliations

  1. Inflammation Research Center, VIB, B-9052, Ghent, Belgium

    Lieselotte Vande Walle, Daniel Jiménez Fernández, Dieter Demon, Naomi Van Laethem, Filip Van Hauwermeiren, Hanne Van Gorp, Nina Van Opdenbosch & Mohamed Lamkanfi

  2. Department of Internal Medicine, Ghent University, Ghent, B-9000, Belgium

    Lieselotte Vande Walle, Daniel Jiménez Fernández, Dieter Demon, Naomi Van Laethem, Filip Van Hauwermeiren, Hanne Van Gorp, Nina Van Opdenbosch & Mohamed Lamkanfi

  3. Medical Biotechnology Center, VIB, B-9000, Ghent, Belgium

    Daniel Jiménez Fernández

  4. Department of Physiological Chemistry, Genentech, South San Francisco, 94080, California, USA

    Nobuhiko Kayagaki

Authors
  1. Lieselotte Vande Walle
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Corresponding author

Correspondence to Mohamed Lamkanfi.

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Extended data figures and tables

Extended Data Figure 1 Description and genotyping of caspase-12−/−V mice.

a, Wild-type and caspase-12−/−S BMDMs were left untreated or treated with 0.5 μg ml−1 LPS for 6 h. Expression of full-length caspase-11 or the truncated caspase-11 Δ110 transcript was determined by RT–PCR. b, Schematic representation of targeting strategy in caspase-12−/−V mice in C57BL/6 ES cells. c, Genotyping of caspase-12−/−V mice by PCR. d, Sequence analysis of genomic region encompassing exon 7 of the caspase-11 gene in caspase-12−/−V mice using the reverse primer described in ref. 6. e, Wild-type and caspase-12−/−V BMDMs were left untreated or treated with 0.5 μg ml−1 LPS for 6 h. Expression of full-length caspase-11 transcript was determined by RT–PCR. f, Wild-type and caspase-12−/−v BMDMs were left untreated or treated with 0.5 μg ml−1 LPS or 200 U ml−1 IFN-γ for 24 h and lysates were immunoblotted for caspase-12, caspase-11, caspase-1 and β-actin. For uncropped gels, see Supplementary Fig. 3.

Extended Data Figure 2 Normal inflammasome signalling in caspase-12−/−G mice.

a, Wild-type and caspase-12−/−G BMDMs were left untreated or treated with 0.5 μg ml−1 LPS. 24 h later, lysates were immunoblotted for caspase-12 and β-actin. b–e, Wild-type and caspase-12−/−G BMDMs were left untreated or primed with 0.5 μg ml−1 LPS for 4 h and subsequently infected with C. rodentium (MOI = 25) for 18 h. Lysates were immunoblotted for caspase-1 (b) and supernatants were analysed for IL-1β (c), IL-18 (d) and LDH (e). f–i, Wild-type and caspase-12−/−G BMDMs were left untreated or primed with 0.5 μg ml−1 LPS for 3 h and then stimulated with 20 μM nigericin for 45 min. Lysates were immunoblotted for caspase-1 (f) and supernatants were analysed for IL-1β (g), IL-18 (h) and LDH (i). j–m, Wild-type and caspase-12−/−G BMDMs were left untreated or infected with S. Typhimurium (MOI = 5) for 3 h. Lysates were immunoblotted for caspase-1 (j) and supernatants analysed for IL-1β (k), IL-18 (l) and LDH (m). Black arrows denote procaspase-1 and white arrows the p20 subunit. Data are representative of results from at least three experiments, and cytokine and LDH data are presented as mean ± s.d. from a single representative experiment, with each condition performed in triplicate. For uncropped gels, see Supplementary Fig. 3.

Extended Data Figure 3 Analysis of inflammasome signalling in splenocytes and caspase-12 expression in macrophages.

a, b, Splenocytes from wild-type and caspase-12−/−V mice were left untreated (Ctrl) or primed with 100 ng ml−1 LPS (a) or 100 ng ml−1 Pam3CSK4 (b). After 24 h, cells were stimulated with 5 mM ATP or 20 μM nigericin for 1 h. Supernatants were analysed for IL-6, IL-1β and IL-18. c, Wild-type and caspase-12−/−V BMDMs were treated with 0.5 μg ml−1 LPS for the indicated times. Caspase-12 mRNA levels were determined by qRT–PCR. d, Analysis of published microarray data set from C57BL/6 BMDMs treated with 10 ng ml−1 LPS11. e, Wild-type and caspase-12−/−V BMDMs were left untreated or treated with 0.5 μg ml−1 LPS for the indicated times and lysates were immunoblotted for caspase-12 and caspase-11. f, g, Raw264.7, J774A.1 cells (f) and wild-type and caspase-12−/−V thioglycolate-elicited peritoneal macrophages (g) were left untreated or treated with 0.5 μg ml−1 LPS for the indicated times and lysates were immunoblotted for caspase-12. The 24 h LPS-treated wild-type and caspase-12−/−V BMDMs were included as controls for specificity. h, Wild-type and caspase-12−/−V thioglycolate-elicited peritoneal macrophages were treated with 0.5 μg ml−1 LPS for 6 h and caspase-12 mRNA levels were determined by qRT–PCR. All data are representative of at least 3 independent experiments, and cytokine and qRT–PCR data are presented as mean ± s.d. from a single representative experiment, with each condition performed in triplicate. For uncropped gels, see Supplementary Fig. 4.

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Vande Walle, L., Jiménez Fernández, D., Demon, D. et al. Does caspase-12 suppress inflammasome activation?. Nature 534, E1–E4 (2016). https://doi.org/10.1038/nature17649

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