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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Glutathione peroxidase 8 negatively regulates caspase-4/11 to protect against colitis
Jye-Lin Hsu1,2, Jen-Wei Chou3, Tzu-Fan Chen1,2
1Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Abstract:
Human caspase-4 and its mouse homolog caspase-11 are receptors for cytoplasmic lipopolysaccharide. Activation of the caspase-4/11-dependent NLRP3 inflammasome is required for innate defense and endotoxic shock, but how caspase-4/11 is modulated remains unclear. Here, we show that mice lacking the oxidative stress sensor glutathione peroxidase 8 (GPx8) are more susceptible to colitis and endotoxic shock, and exhibit reduced richness and diversity of the gut microbiome. C57BL/6 mice that underwent adoptive cell transfer of GPx8-deficient macrophages displayed a similar phenotype of enhanced colitis, indicating a critical role of GPx8 in macrophages. GPx8 binds covalently to caspase-4/11 via disulfide bonding between cysteine 79 of GPx8 and cysteine 118 of caspase-4 and thus restrains caspase-4/11 activation, while GPx8 deficiency leads to caspase-4/11-induced inflammation during colitis and septic shock. Inhibition of caspase-4/11 activation with small molecules reduces the severity of colitis in GPx8-deficient mice. Notably, colonic tissues from patients with ulcerative colitis display low levels of Gpx8 and high caspase-4 expression. In conclusion, these results suggest that GPx8 protects against colitis by negatively regulating caspase-4/11 activity.
Insights
Glutathione peroxidase 8 (GPx8) restrains caspase-4/11 activation, preventing inflammation. GPx8 deficiency exacerbates colitis and endotoxic shock, highlighting GPx8
Area of Science:
- Immunology
- Oxidative Stress Biology
- Microbiome Research
Background:
- Caspase-4/11 are key receptors for cytoplasmic lipopolysaccharide, activating the NLRP3 inflammasome.
- The precise regulation of caspase-4/11 activity in innate immunity and disease remains incompletely understood.
Purpose of the Study:
- To investigate the role of glutathione peroxidase 8 (GPx8) in modulating caspase-4/11 activation and its impact on inflammatory diseases.
- To elucidate the mechanism by which GPx8 influences caspase-4/11 activity.
Main Methods:
- Utilized knockout mice lacking GPx8 and performed adoptive cell transfer experiments with GPx8-deficient macrophages.
- Investigated the molecular interaction between GPx8 and caspase-4/11 using biochemical assays.
- Analyzed colonic tissues from patients with ulcerative colitis.
Main Results:
- GPx8 deficiency in mice led to increased susceptibility to colitis and endotoxic shock, accompanied by gut dysbiosis.
- GPx8 directly binds to and inhibits caspase-4/11 via disulfide bonding, preventing excessive inflammation.
- GPx8 inhibition or deficiency resulted in heightened caspase-4/11-mediated inflammation.
- Reduced GPx8 and elevated caspase-4 expression were observed in colonic tissues of ulcerative colitis patients.
Conclusions:
- GPx8 acts as a critical negative regulator of caspase-4/11 activation.
- GPx8 plays a protective role in preventing colitis and endotoxic shock by controlling inflammatory responses.
- GPx8 represents a potential therapeutic target for inflammatory conditions like ulcerative colitis.
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