Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice
Abstract Background Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFβ1) is upregulated due to liver failure in mice and inhibiting circulating TGFβ...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1455-y |
| _version_ | 1798043678246174720 |
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| author | Matthew McMillin Stephanie Grant Gabriel Frampton Anca D. Petrescu Elaina Williams Brandi Jefferson Alison Thomas Ankita Brahmaroutu Sharon DeMorrow |
| author_facet | Matthew McMillin Stephanie Grant Gabriel Frampton Anca D. Petrescu Elaina Williams Brandi Jefferson Alison Thomas Ankita Brahmaroutu Sharon DeMorrow |
| author_sort | Matthew McMillin |
| collection | DOAJ |
| description | Abstract Background Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFβ1) is upregulated due to liver failure in mice and inhibiting circulating TGFβ reduced HE progression. However, the specific contributions of TGFβ1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFβ1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. Methods C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFβR2) null mice (TGFβR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFβ1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFβ1 (anti-TGFβ1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFβ1 signaling in HT-22 and EOC-20 cells. Results TGFβ1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFβ1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFβR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFβ1 or in TGFβR2ΔNeu mice. TGFβ1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. Conclusion Increased circulating TGFβ1 following acute liver failure results in activation of neuronal TGFβR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE. |
| first_indexed | 2024-04-11T22:52:27Z |
| format | Article |
| id | doaj.art-1cdba4273ef84def81caad854bf28d94 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T22:52:27Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-1cdba4273ef84def81caad854bf28d942022-12-22T03:58:32ZengBMCJournal of Neuroinflammation1742-20942019-04-0116111510.1186/s12974-019-1455-yElevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in miceMatthew McMillin0Stephanie Grant1Gabriel Frampton2Anca D. Petrescu3Elaina Williams4Brandi Jefferson5Alison Thomas6Ankita Brahmaroutu7Sharon DeMorrow8Central Texas Veterans Health Care SystemCentral Texas Veterans Health Care SystemCentral Texas Veterans Health Care SystemCentral Texas Veterans Health Care SystemCentral Texas Veterans Health Care SystemCentral Texas Veterans Health Care SystemDepartment of Medical Physiology, College of Medicine, Texas A&M University Health Science CenterDepartment of Medical Physiology, College of Medicine, Texas A&M University Health Science CenterCentral Texas Veterans Health Care SystemAbstract Background Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFβ1) is upregulated due to liver failure in mice and inhibiting circulating TGFβ reduced HE progression. However, the specific contributions of TGFβ1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFβ1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. Methods C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFβR2) null mice (TGFβR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFβ1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFβ1 (anti-TGFβ1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFβ1 signaling in HT-22 and EOC-20 cells. Results TGFβ1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFβ1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFβR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFβ1 or in TGFβR2ΔNeu mice. TGFβ1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. Conclusion Increased circulating TGFβ1 following acute liver failure results in activation of neuronal TGFβR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.http://link.springer.com/article/10.1186/s12974-019-1455-yAcute liver failureAzoxymethaneMicrogliaNeuroinflammationNecrosis |
| spellingShingle | Matthew McMillin Stephanie Grant Gabriel Frampton Anca D. Petrescu Elaina Williams Brandi Jefferson Alison Thomas Ankita Brahmaroutu Sharon DeMorrow Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice Journal of Neuroinflammation Acute liver failure Azoxymethane Microglia Neuroinflammation Necrosis |
| title | Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| title_full | Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| title_fullStr | Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| title_full_unstemmed | Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| title_short | Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| title_sort | elevated circulating tgfβ1 during acute liver failure activates tgfβr2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice |
| topic | Acute liver failure Azoxymethane Microglia Neuroinflammation Necrosis |
| url | http://link.springer.com/article/10.1186/s12974-019-1455-y |
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