| First Author | Manakkat Vijay GK | Year | 2019 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 8 |
| Issue | 4 | Pages | 609-623 |
| PubMed ID | 31401214 | Mgi Jnum | J:293329 |
| Mgi Id | MGI:6452552 | Doi | 10.1016/j.jcmgh.2019.08.002 |
| Citation | Manakkat Vijay GK, et al. (2019) Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9. Cell Mol Gastroenterol Hepatol 8(4):609-623 |
| abstractText | BACKGROUND & AIM: Ammonia is central in the pathogenesis of brain edema in acute liver failure (ALF) with infection and systemic inflammation expediting development of intracranial hypertension (ICH). Patients with acetaminophen-induced ALF have increased neutrophil TLR9 expression which can be induced by ammonia. We determined whether ammonia-induced brain edema and immune dysfunction are mediated by TLR9 and if this could be prevented in a TLR9-deficient mouse model. METHODS: Ammonium acetate (NH4-Ac; 4mmol/kg) was injected intraperitoneally in wild type (WT), Tlr9(-/-) and Lysm-Cre Tlr9(fl/fl) mice (TLR9 absent in neutrophils and macrophages including Kupffer cells) and compared to controls. Six hours after NH4-Ac injection, intracellular cytokine production was determined in splenic macrophages, CD4(+) and CD8(+) T cells. Brain water (BW) and total plasma DNA (tDNA) were also measured. The impact of the TLR9 antagonist ODN2088 (50mug/mouse) was evaluated. RESULTS: Following NH4-Ac injection, BW, macrophage and T cell cytokine production increased (P < .0001) in WT but not Tlr9(-/-) mice (P < .001). ODN2088 inhibited macrophage and T cell cytokine production (P < .05) and prevented an increase in BW (P < .0001). Following NH4-Ac injection, macrophage cytokine production and BW were ameliorated in Lysm-Cre Tlr9(fl/fl) mice compared to WT mice (P < .05) but there was no difference compared to Tlr9(-/-) mice. Following NH4-Ac injection, plasma tDNA levels increased in WT and Tlr9(-/-) mice (P < .05) suggesting that TLR9 may be activated by DNA released from ammonia-stimulated cells. CONCLUSION: Ammonia-induced brain edema requires macrophage and T cell expression of TLR9. Amelioration of brain edema and lymphocyte cytokine production by ODN2088 supports exploration of TLR9 antagonism in early ALF to prevent progression to ICH. |
