Comment on “Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury”

Hartmut Jaeschke and C. David Williams
J Immunol December 15, 2011, 187 (12) 6168; DOI: https://doi.org/10.4049/jimmunol.1190076

After reading the article by Dear et al. (1) in the September 15 issue of The Journal of Immunology, we have several serious concerns. First, there was extreme variation of injury in both wild-type and cyclophilin A-deficient mice with >50% of animals having no injury. We assume that this is caused by the use of both male and female mice, which substantially differ in their susceptibility to acetaminophen. As the composition of the individual groups is not disclosed, it is difficult to interpret these data. The authors also conclude that there was no difference in metabolic activation based on similar glutathione levels at 6 h. However, this time point is too late to justify this conclusion (2). Furthermore, acetaminophen caused dramatically less injury in IgG-treated mice compared to wild-type animals. As a pretreatment regimen with immunological agents was used, this may have caused impaired metabolic activation or enhanced resistance to cell injury (3).

The second concern is the role of damage-associated molecular patterns (DAMPs) in the pathophysiology. DAMPs act on immune cells to generate cytokines, which activate neutrophils during the first 24 h after acetaminophen overdose (3). Thus, if cyclophilin A mediates acetaminophen-induced injury, this mediation would depend on a neutrophil-induced injury. However, neutrophils are not activated after acetaminophen overdose (4) and a large number of diverse intervention strategies against neutrophils did not result in any effect on liver injury (4–7). The data of the few studies that claim involvement of neutrophils or inflammatory mediators such as IL-1β can be explained by off-target effects of the immunological agents (8) or are simply not reproducible (9, 10). Acetaminophen-induced liver injury is determined by intracellular signaling events in hepatocytes (11); any involvement of DAMPs released by necrotic cells has to modulate these pathways in hepatocytes, not neutrophils, to have an impact on the overall injury (3).

References

    1. Dear J. W.,
    2. K. J. Simpson,
    3. M. P. J. Nicolai,
    4. J. H. Catterson,
    5. J. Street,
    6. T. Huizinga,
    7. D. G. Craig,
    8. K. Dhaliwal,
    9. S. Webb,
    10. D. N. Bateman,
    11. D. J. Webb
    . 2011. Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury. J. Immunol. 187: 3347–3352.
    1. Jaeschke H.,
    2. M. R. McGill,
    3. C. D. Williams,
    4. A. Ramachandran
    . 2011. Acetaminophen hepatotoxicity—a clinically relevant model to test the efficacy of natural products. Life Sci. 88: 737–745.
    1. Jaeschke H.,
    2. C. D. Williams,
    3. A. Ramachandran,
    4. M. L. Bajt
    . 2011. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int. DOI: 10.1111/j.1478-3231.2011.02501.x.
    1. Williams C. D.,
    2. M. L. Bajt,
    3. A. Farhood,
    4. H. Jaeschke
    . 2010. Acetaminophen-induced hepatic neutrophil recruitment and liver injury in CD18-deficient mice. Liver Int. 30: 1280–1292.
    1. Lawson J. A.,
    2. A. Farhood,
    3. R. D. Hopper,
    4. M. L. Bajt,
    5. H. Jaeschke
    . 2000. The hepatic inflammatory response after acetaminophen overdose: The role of neutrophils. Toxicol. Sci. 54: 509–516.
    1. James L. P.,
    2. S. S. McCullough,
    3. T. R. Knight,
    4. H. Jaeschke,
    5. J. A. Hinson
    . 2003. Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic. Res. 37: 1289–1297.
    1. Cover C.,
    2. J. Liu,
    3. A. Farhood,
    4. E. Malle,
    5. M. P. Waalkes,
    6. M. L. Bajt,
    7. H. Jaeschke
    . 2006. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol. Appl. Pharmacol. 216: 98–107.
    1. Jaeschke H.,
    2. J. Liu
    . 2007. Neutrophil depletion protects against murine acetaminophen hepatotoxicity: Another perspective. Hepatology 45: 1588–1589.
    1. Williams C. D.,
    2. A. Farhood,
    3. H. Jaeschke
    . 2010. Role of caspase-1 and interleukin-1β in acetaminophen-induced hepatic inflammation and liver injury. Toxicol. Appl. Pharmacol. 247: 169–178.
    1. Williams C. D.,
    2. D. J. Antoine,
    3. P. J. Shaw,
    4. C. Benson,
    5. A. Farhood,
    6. D. P. Williams,
    7. T. D. Kanneganti,
    8. B. K. Park,
    9. H. Jaeschke
    . 2011. Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury. Toxicol. Appl. Pharmacol. 252: 289–297.
    1. Jaeschke H.,
    2. M. L. Bajt
    . 2006. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol. Sci. 89: 31–41.