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Updated: Jun 20, 2026
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Caspase-12 and the inflammatory response to Yersinia pestis
Bart Ferwerda1, Matthew B B McCall, Maaike C de Vries
1Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. E.ferwerda@aig.umcn.nl
Background:
Caspase-12 functions as an antiinflammatory enzyme inhibiting caspase-1 and the NOD2/RIP2 pathways. Due to increased susceptibility to sepsis in individuals with functional caspase-12, an early-stop mutation leading to the loss of caspase-12 has replaced the ancient genotype in Eurasia and a significant proportion of individuals from African populations. In African-Americans, it has been shown that caspase-12 inhibits the pro-inflammatory cytokine production.
Methodology/Principal Findings:
We assessed whether similar mechanisms are present in African individuals, and whether evolutionary pressures due to plague may have led to the present caspase-12 genotype population frequencies. No difference in cytokine induction through the caspase-1 and/or NOD2/RIP2 pathways was observed in two independent African populations, among individuals with either an intact or absent caspase-12. In addition, stimulations with Yersinia pestis and two other species of Yersinia were preformed to investigate whether caspase-12 modulates the inflammatory reaction induced by Yersinia. We found that caspase-12 did not modulate cytokine production induced by Yersinia spp.
Conclusions:
Our experiments demonstrate for the first time the involvement of the NOD2/RIP2 pathway for recognition of Yersinia. However, caspase-12 does not modulate innate host defense against Y. pestis and alternative explanations for the geographical distribution of caspase-12 should be sought.
Insights
Caspase-12 loss does not affect inflammatory responses to Yersinia in African populations, despite its anti-inflammatory role. Evolutionary reasons for caspase-12 genotype frequencies require further investigation beyond plague susceptibility.
Area of Science:
- Immunology
- Genetics
- Evolutionary Biology
Background:
- Caspase-12 acts as an anti-inflammatory enzyme, inhibiting caspase-1 and NOD2/RIP2 pathways.
- Loss-of-function mutations in caspase-12 are prevalent in Eurasian and some African populations due to sepsis susceptibility.
- Caspase-12 has been shown to inhibit pro-inflammatory cytokine production in African-Americans.
Purpose of the Study:
- To investigate if similar anti-inflammatory mechanisms of caspase-12 are present in African populations.
- To explore evolutionary pressures, such as plague, that may have influenced caspase-12 genotype frequencies.
- To determine if caspase-12 modulates inflammatory responses to Yersinia species.
Main Methods:
- Assessed cytokine induction via caspase-1 and NOD2/RIP2 pathways in two African populations with intact or absent caspase-12.
- Stimulated cells with Yersinia pestis and other Yersinia species.
- Analyzed inflammatory reactions and cytokine production.
Main Results:
- No significant difference in cytokine induction was observed between individuals with intact or absent caspase-12.
- Caspase-12 did not modulate cytokine production in response to Yersinia spp. stimulation.
- The NOD2/RIP2 pathway was confirmed to be involved in Yersinia recognition.
Conclusions:
- Caspase-12 does not appear to modulate innate host defense against Yersinia pestis.
- The NOD2/RIP2 pathway plays a role in recognizing Yersinia.
- Alternative explanations for the geographical distribution of caspase-12 genotypes should be explored.
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