Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
|
| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X19300992 |
| _version_ | 1828321750269558784 |
|---|---|
| author | Godhev Kumar Manakkat Vijay Changyun Hu Jian Peng Irma Garcia-Martinez Rafaz Hoque Rejina Mariam Verghis Yun Ma Wajahat Zafar Mehal Debbie Lindsay Shawcross Li Wen |
| author_facet | Godhev Kumar Manakkat Vijay Changyun Hu Jian Peng Irma Garcia-Martinez Rafaz Hoque Rejina Mariam Verghis Yun Ma Wajahat Zafar Mehal Debbie Lindsay Shawcross Li Wen |
| author_sort | Godhev Kumar Manakkat Vijay |
| collection | DOAJ |
| description | 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 < .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 Tlr9fl/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. Keywords: Ammonia, Brain edema, Immune dysfunction, Toll-like receptor 9 |
| first_indexed | 2024-04-13T18:30:22Z |
| format | Article |
| id | doaj.art-6b3254df6bd34e1c9032ffce28c2bbb3 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-13T18:30:22Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-6b3254df6bd34e1c9032ffce28c2bbb32022-12-22T02:35:05ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2019-01-0184609623Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9SummaryGodhev Kumar Manakkat Vijay0Changyun Hu1Jian Peng2Irma Garcia-Martinez3Rafaz Hoque4Rejina Mariam Verghis5Yun Ma6Wajahat Zafar Mehal7Debbie Lindsay Shawcross8Li Wen9Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom; Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutSection of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutSection of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutSection of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutSection of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutWelcome Wolfson Institute of Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queens University, Belfast, United KingdomLiver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United KingdomSection of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, ConnecticutLiver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom; Correspondence Address correspondence to: Debbie Lindsay Shawcross, BSc, MBBS, PhD, Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital Campus, Denmark Hill, London, SE5 9RS United Kingdom. fax: +44 (0)20 3299 3167.Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Li Wen, MD, PhD, Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, PO Box 208020, 333 Cedar Street, New Haven, Connecticut 06520. fax: (203) 737–5558.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 < .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 Tlr9fl/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. Keywords: Ammonia, Brain edema, Immune dysfunction, Toll-like receptor 9http://www.sciencedirect.com/science/article/pii/S2352345X19300992 |
| spellingShingle | Godhev Kumar Manakkat Vijay Changyun Hu Jian Peng Irma Garcia-Martinez Rafaz Hoque Rejina Mariam Verghis Yun Ma Wajahat Zafar Mehal Debbie Lindsay Shawcross Li Wen Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary Cellular and Molecular Gastroenterology and Hepatology |
| title | Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary |
| title_full | Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary |
| title_fullStr | Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary |
| title_full_unstemmed | Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary |
| title_short | Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9Summary |
| title_sort | ammonia induced brain edema requires macrophage and t cell expression of toll like receptor 9summary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X19300992 |
| work_keys_str_mv | AT godhevkumarmanakkatvijay ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT changyunhu ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT jianpeng ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT irmagarciamartinez ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT rafazhoque ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT rejinamariamverghis ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT yunma ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT wajahatzafarmehal ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT debbielindsayshawcross ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary AT liwen ammoniainducedbrainedemarequiresmacrophageandtcellexpressionoftolllikereceptor9summary |