Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function
Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02623/full |
| _version_ | 1818908955495104512 |
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| author | Odelia Mouhadeb Odelia Mouhadeb Shani Ben Shlomo Keren Cohen Keren Cohen Inbal Farkash Shlomo Gruber Nitsan Maharshak Zamir Halpern Ezra Burstein Ezra Burstein Nathan Gluck Chen Varol Chen Varol |
| author_facet | Odelia Mouhadeb Odelia Mouhadeb Shani Ben Shlomo Keren Cohen Keren Cohen Inbal Farkash Shlomo Gruber Nitsan Maharshak Zamir Halpern Ezra Burstein Ezra Burstein Nathan Gluck Chen Varol Chen Varol |
| author_sort | Odelia Mouhadeb |
| collection | DOAJ |
| description | Ly6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD. |
| first_indexed | 2024-12-19T22:19:14Z |
| format | Article |
| id | doaj.art-c4d289a421fd4b6ab0ae01ed81d7e8d8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T22:19:14Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c4d289a421fd4b6ab0ae01ed81d7e8d82022-12-21T20:03:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02623418176Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier FunctionOdelia Mouhadeb0Odelia Mouhadeb1Shani Ben Shlomo2Keren Cohen3Keren Cohen4Inbal Farkash5Shlomo Gruber6Nitsan Maharshak7Zamir Halpern8Ezra Burstein9Ezra Burstein10Nathan Gluck11Chen Varol12Chen Varol13The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United StatesThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, IsraelLy6Chi monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6Chi monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6Chi monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6Chi monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6Chi monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6Chi monocytes. In consistence with these results, COMMD10-deficiency in Ly6Chi monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6Chi monocytes and their corresponding human CD14hi monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6Chi monocyte inflammasome activity during systemic inflammation and IBD.https://www.frontiersin.org/article/10.3389/fimmu.2018.02623/fullCOMMD10Ly6Chi monocytesinflammasomesystemic inflammationcolitis |
| spellingShingle | Odelia Mouhadeb Odelia Mouhadeb Shani Ben Shlomo Keren Cohen Keren Cohen Inbal Farkash Shlomo Gruber Nitsan Maharshak Zamir Halpern Ezra Burstein Ezra Burstein Nathan Gluck Chen Varol Chen Varol Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function Frontiers in Immunology COMMD10 Ly6Chi monocytes inflammasome systemic inflammation colitis |
| title | Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function |
| title_full | Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function |
| title_fullStr | Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function |
| title_full_unstemmed | Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function |
| title_short | Impaired COMMD10-Mediated Regulation of Ly6Chi Monocyte-Driven Inflammation Disrupts Gut Barrier Function |
| title_sort | impaired commd10 mediated regulation of ly6chi monocyte driven inflammation disrupts gut barrier function |
| topic | COMMD10 Ly6Chi monocytes inflammasome systemic inflammation colitis |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02623/full |
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