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Ammonia-induced brain edema requires macrophage and T cell expression of Toll-like receptor 9

Research output: Contribution to journalArticle

Godhev Kumar Manakkat Vijay, Changyun Hu, Jian Peng, Irma Garcia Martinez, Rafaz Hoque, Rejina Mariam Verghis, Yun Ma, Wajahat Mehal, Debbie Lindsay Shawcross, Li Wen

Original languageEnglish
JournalCellular and molecular gastroenterology and hepatology
Early online date8 Aug 2019
DOIs
Publication statusE-pub ahead of print - 8 Aug 2019

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Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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Abstract

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 Tlr9fl/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 (50μg/mouse) was evaluated.

RESULTS: Following NH4-Ac injection, BW, macrophage and T cell cytokine production increased (p<0.0001) in WT but not Tlr9-/- mice (p<0.001). ODN2088 inhibited macrophage and T cell cytokine production (p<0.05) and prevented an increase in BW (p<0.0001). Following NH4-Ac injection, macrophage cytokine production and BW were ameliorated in Lysm-Cre Tlr9fl/fl mice compared to WT mice (p<0.05) but there was no difference compared to Tlr9-/- mice. Following NH4-Ac injection, plasma tDNA levels increased in WT and Tlr9-/- mice (p<0.05) 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.

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