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Blocking TLR9 may halt brain edema in acute liver failure

Key clinical point: A toll-like receptor 9 (TLR9) antagonist may one day be used to combat brain edema in acute liver failure.

Major finding: Compared with untreated wild-type mice, wild-type mice treated immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse) did not develop significant brain edema (P less than .0001).

Study details: A mouse model study involving wild-type mice and TLR9 knockout mice.

Disclosures: The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

Citation:

Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

Commentary:

Acute liver failure is a devastating disease, which has a high mortality burden and often requires liver transplant. One of the major complications is cerebral edema that leads to encephalopathy and could be fatal. These brain changes are accompanied by inflammation, immune activation, and hyperammonemia, but further mechanistic approaches are needed.

The paper by Vijay et al. in this issue of Cellular and Molecular Gastroenterology and Hepatology studies the role of toll-like receptor 9 (TLR9) as a mediator of cerebral edema in a model of hyperammonemia. The authors use a novel combination of ammonium acetate and TLR9–/– mice to induce hyperammonemia while maintaining liver function, allowing direct evaluation of the receptor knockout’s effect on the subsequent development of brain edema. Further nuance is achieved by use of TLR9fl/fl mice crossed with mice expressing Cre recombinase under the control of the lysozyme promoter, generating macrophage and neutrophil conditional knockouts of TLR9. The results clearly demonstrate the absence of TLR9 prevents ammonia-induced increases in brain water, proinflammatory cytokine production, and hepatocyte swelling, which was reversed with the TLR9 antagonist ODN2088.

This data adds to the growing literature about the interaction between immune dysfunction and brain diseases such as schizophrenia, autism, depression, and multiple sclerosis. However, further studies in models of brain edema with concomitant liver failure, which are closer to the human disease process, are needed. This exciting investigation of neuroimmune regulation of brain edema could set the basis for new therapeutic options for the prevention and treatment of this feared complication of acute liver failure.

Jasmohan S. Bajaj, MD, AGAF, is professor in the division of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University, Richmond. He reported no conflicts of interest.