Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis
De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting reg...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01612/full |
| _version_ | 1818030478185201664 |
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| author | Adam S. Arterbery Jie Yao Andrew Ling Yaron Avitzur Mercedes Martinez Steven Lobritto Yanhong Deng Gan Geliang Sameet Mehta Guilin Wang James Knight Udeme D. Ekong |
| author_facet | Adam S. Arterbery Jie Yao Andrew Ling Yaron Avitzur Mercedes Martinez Steven Lobritto Yanhong Deng Gan Geliang Sameet Mehta Guilin Wang James Knight Udeme D. Ekong |
| author_sort | Adam S. Arterbery |
| collection | DOAJ |
| description | De novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways. |
| first_indexed | 2024-12-10T05:36:13Z |
| format | Article |
| id | doaj.art-97b419beb89e4aeb96c3401a10f1d32a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T05:36:13Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-97b419beb89e4aeb96c3401a10f1d32a2022-12-22T02:00:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-07-01910.3389/fimmu.2018.01612380876Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune HepatitisAdam S. Arterbery0Jie Yao1Andrew Ling2Yaron Avitzur3Mercedes Martinez4Steven Lobritto5Yanhong Deng6Gan Geliang7Sameet Mehta8Guilin Wang9James Knight10Udeme D. Ekong11Pediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United StatesPediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United StatesPediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United StatesGastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, ON, CanadaPediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, United StatesPediatric Gastroenterology, Hepatology, and Nutrition, Columbia University, New York, NY, United StatesYale Center for Analytical Sciences, New Haven, CT, United StatesYale Center for Analytical Sciences, New Haven, CT, United StatesYale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United StatesYale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United StatesYale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, United StatesPediatric Gastroenterology and Hepatology, Yale University, New Haven, CT, United StatesDe novo autoimmune hepatitis (DAIH) is an important cause of late allograft dysfunction following liver transplantation, but its cause and underlying pathogenesis remains unclear. We sought to identify specific innate and adaptive immune mechanisms driving the pro-inflammatory cytokine secreting regulatory T cell (Treg) phenotype in DAIH and determine if modulation of these pathways could resolve the inflammatory milieu observed in the livers of patients with DAIH. Here, we demonstrate toll-like receptors (TLRs) 2- and 4-mediated inflammasome activation in CD14++ monocytes, a finding that is key to maintaining dysfunctional Tregs in patients with DAIH. Furthermore, silencing of TLR 2 and 4 in CD14++ monocytes prevented activation of the inflammasome and significantly decreased IFN-γ production by FOXP3+ Tregs. We also observed significantly increase in expression of tumor necrosis factor α-induced protein 3 (TNFAIP3), a negative regulator of the NLRP3 Inflammasome, in monocytes/macrophages of liver transplant subjects who have normal allograft function and do not have DAIH. TNFAIP3 expression was virtually absent in monocytes/macrophages of patients with DAIH. Our findings suggest that autoimmunity in DAIH is promoted by CD14++ monocytes predominantly through activation of inflammatory signaling pathways.https://www.frontiersin.org/article/10.3389/fimmu.2018.01612/fullinnate immunitytoll-like receptorsinflammasomeTh1 regulatory T cellsliver transplantationCD14++ monocytes |
| spellingShingle | Adam S. Arterbery Jie Yao Andrew Ling Yaron Avitzur Mercedes Martinez Steven Lobritto Yanhong Deng Gan Geliang Sameet Mehta Guilin Wang James Knight Udeme D. Ekong Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis Frontiers in Immunology innate immunity toll-like receptors inflammasome Th1 regulatory T cells liver transplantation CD14++ monocytes |
| title | Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis |
| title_full | Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis |
| title_fullStr | Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis |
| title_full_unstemmed | Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis |
| title_short | Inflammasome Priming Mediated via Toll-Like Receptors 2 and 4, Induces Th1-Like Regulatory T Cells in De Novo Autoimmune Hepatitis |
| title_sort | inflammasome priming mediated via toll like receptors 2 and 4 induces th1 like regulatory t cells in de novo autoimmune hepatitis |
| topic | innate immunity toll-like receptors inflammasome Th1 regulatory T cells liver transplantation CD14++ monocytes |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01612/full |
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