Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis
Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 cell exp...
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| Published in: | Science translational medicine Vol. 15; no. 698; p. eabn0736 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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31.05.2023
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| ISSN: | 1946-6242, 1946-6242 |
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| Abstract | Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1
) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1
cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1
cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (
) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1
cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by
deletion in
-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1
cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis. |
|---|---|
| AbstractList | Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis. Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1 ) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D ( ) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by deletion in -expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis. |
| Author | Finnie, Sarah Ferenbach, David A O'Sullivan, Eoin D Hughes, Jeremy Baird, David P Campbell, Ross Gordon-Keylock, Sabrina Jia, Siyang Laird, Alexander Carvalho, Cyril Leung, Steve Wilflingseder, Julia Denby, Laura Matchett, Kylie P Mylonas, Katie J Willi, Michaela Docherty, Marie-Helena Chandra, Tamir Medvinsky, Alexander Gallagher, Kevin M Bonventre, Joseph V Xin, Cuiyan Reck, Maximilian Pisco, Angela Walker, Alexander D Kirschner, Kristina Waddell, Scott H Conway, Bryan R Boulter, Luke Henderson, Neil C |
| Author_xml | – sequence: 1 givenname: Eoin D orcidid: 0000-0002-7709-6595 surname: O'Sullivan fullname: O'Sullivan, Eoin D organization: Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia – sequence: 2 givenname: Katie J orcidid: 0000-0002-7324-4597 surname: Mylonas fullname: Mylonas, Katie J organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 3 givenname: Cuiyan surname: Xin fullname: Xin, Cuiyan organization: Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA – sequence: 4 givenname: David P orcidid: 0000-0002-6338-3788 surname: Baird fullname: Baird, David P organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 5 givenname: Cyril orcidid: 0000-0001-7125-3521 surname: Carvalho fullname: Carvalho, Cyril organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 6 givenname: Marie-Helena surname: Docherty fullname: Docherty, Marie-Helena organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 7 givenname: Ross orcidid: 0000-0003-2298-9887 surname: Campbell fullname: Campbell, Ross organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 8 givenname: Kylie P orcidid: 0000-0001-8710-7721 surname: Matchett fullname: Matchett, Kylie P organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 9 givenname: Scott H orcidid: 0000-0002-8696-5481 surname: Waddell fullname: Waddell, Scott H organization: Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK – sequence: 10 givenname: Alexander D surname: Walker fullname: Walker, Alexander D organization: Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK – sequence: 11 givenname: Kevin M orcidid: 0000-0001-5485-5336 surname: Gallagher fullname: Gallagher, Kevin M organization: Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK – sequence: 12 givenname: Siyang orcidid: 0009-0005-6614-3922 surname: Jia fullname: Jia, Siyang organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 13 givenname: Steve orcidid: 0000-0002-8366-2880 surname: Leung fullname: Leung, Steve organization: Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK – sequence: 14 givenname: Alexander orcidid: 0000-0002-7296-025X surname: Laird fullname: Laird, Alexander organization: Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK – sequence: 15 givenname: Julia orcidid: 0000-0002-0230-9349 surname: Wilflingseder fullname: Wilflingseder, Julia organization: Department of Physiology and Pathophysiology, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria – sequence: 16 givenname: Michaela orcidid: 0000-0002-2248-1998 surname: Willi fullname: Willi, Michaela organization: Laboratory of Genetics and Physiology, NIDDK, NIH, Bethesda, MD 20892, USA – sequence: 17 givenname: Maximilian surname: Reck fullname: Reck, Maximilian organization: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 18 givenname: Sarah orcidid: 0009-0006-6695-970X surname: Finnie fullname: Finnie, Sarah organization: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 19 givenname: Angela orcidid: 0000-0003-0142-2355 surname: Pisco fullname: Pisco, Angela organization: Chan Zuckerberg Biohub, San Francisco, CA 94158, USA – sequence: 20 givenname: Sabrina surname: Gordon-Keylock fullname: Gordon-Keylock, Sabrina organization: Centre for Regenerative Medicine. University of Edinburgh, Edinburgh EH16 4UU, UK – sequence: 21 givenname: Alexander surname: Medvinsky fullname: Medvinsky, Alexander organization: Centre for Regenerative Medicine. University of Edinburgh, Edinburgh EH16 4UU, UK – sequence: 22 givenname: Luke orcidid: 0000-0002-7954-6705 surname: Boulter fullname: Boulter, Luke organization: Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK – sequence: 23 givenname: Neil C orcidid: 0000-0002-2273-4094 surname: Henderson fullname: Henderson, Neil C organization: Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK – sequence: 24 givenname: Kristina orcidid: 0000-0001-7607-8670 surname: Kirschner fullname: Kirschner, Kristina organization: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK – sequence: 25 givenname: Tamir orcidid: 0000-0002-7935-317X surname: Chandra fullname: Chandra, Tamir organization: Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK – sequence: 26 givenname: Bryan R surname: Conway fullname: Conway, Bryan R organization: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 27 givenname: Jeremy orcidid: 0000-0002-3470-0422 surname: Hughes fullname: Hughes, Jeremy organization: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 28 givenname: Laura orcidid: 0000-0003-1277-708X surname: Denby fullname: Denby, Laura organization: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK – sequence: 29 givenname: Joseph V orcidid: 0000-0001-7144-386X surname: Bonventre fullname: Bonventre, Joseph V organization: Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA – sequence: 30 givenname: David A orcidid: 0000-0002-9202-1428 surname: Ferenbach fullname: Ferenbach, David A organization: Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA |
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| References | 37386290 - Nat Rev Nephrol. 2023 Aug;19(8):478. doi: 10.1038/s41581-023-00735-8. |
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| SubjectTerms | Animals Fibrosis Hedgehog Proteins - metabolism Humans Inflammation Mice NF-kappa B Renal Insufficiency, Chronic Tumor Necrosis Factors Zinc Finger Protein GLI1 |
| Title | Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis |
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