Does caspase-11 pyroptosis feed atherosclerosis?

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Integrating GEO data, ox-LDL macrophages, and ApoE−/− mice, the authors show caspase-11/GSDMD pyroptosis inflames plaques; deleting caspase-11 or AAV-suppressing GSDMD shrinks lesions, and human caspase-4 mRNA tracks coronary severity.

Source

Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis

Jiang M, Sun X, Liu S, et al. · Frontiers in pharmacology · 2021

doi.org/10.3389/fphar.2021.657486 Read the full paper ↗54 citationscc by

Study at a glance

Design: Animal / in-vitro — GEO transcriptomics + ox-LDL macrophages + ApoE−/− mice ± caspase-11 deletion or AAV-GSDMD knockdown; supportive CHD PBMC qPCR (n = 28)
N: N=28 · 28 coronary arteriography patients for PBMC caspase-4; ApoE−/− mice on 12-week HFHC diet plus macrophage cultures
Population: ApoE−/− mice, ox-LDL-treated peritoneal macrophages, and nonacute CHD patients’ PBMCs
Outcome: Caspase-11/GSDMD pyroptosis, plaque volume/macrophage infiltrate, and PBMC caspase-4 vs coronary severity

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What they did

Mined GEO with hyperlipidemic-mouse and ox-LDL macrophage transcriptomes, measured caspase-4/GSDMD in PBMCs from 28 CHD patients, fed ApoE−/− mice HFHC for 12 weeks with caspase-11 deletion or AAV-GSDMD knockdown, and probed macrophage pyroptosis in vitro.

What they found

Caspase-4/11–GSDMD signaling was activated. Human PBMC caspase-4 and GSDMD were upregulated and caspase-4 correlated with coronary severity/SYNTAX. Caspase-11 deletion or GSDMD AAV knockdown cut plaque volume and macrophage infiltration; macrophage inflammation was partly GSDMD-pyroptosis dependent.

The limits

What it doesn't show

Mouse HFHC atherosclerosis and n = 28 PBMCs do not prove that caspase-11 inhibitors treat human CAD; human data are associative mRNA, not a clinical outcomes trial.

Key terms

Pyroptosis: Gasdermin-pore inflammatory cell death; here GSDMD in macrophages.
Caspase-11 (mouse) / caspase-4 (human): Noncanonical inflammasome caspases activated by oxidized lipids in this model.
GSDMD: Gasdermin D, the pore-forming executioner of pyroptosis.
ApoE−/− HFHC: Atherosclerosis-prone mice on a 12-week high-fat/high-cholesterol diet.
ox-LDL: Oxidized LDL used to challenge peritoneal macrophages.
SYNTAX score: Angiographic complexity score correlated with PBMC caspase-4 mRNA.

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Human PBMC n was:

Common questions

Human sample for PBMC mRNA?

n = 28 patients at Third Xiangya Hospital.

Mouse diet?

HFHC for twelve weeks in 8- to 10-week-old male ApoE−/− mice.

What reduced plaques in vivo?

Caspase-11 deletion or AAV suppression of GSDMD.

Human caspase-4 related to?

Severity of coronary lesions / SYNTAX score.