CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling
Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cel...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.161487 |
| _version_ | 1797634323500761088 |
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| author | Marta Bueno Jazmin Calyeca Timur Khaliullin Megan P. Miller Diana Alvarez Lorena Rosas Judith Brands Christian Baker Amro Nasser Stephanie Shulkowski August Mathien Nneoma Uzoukwu John Sembrat Brenton G. Mays Kaitlin Fiedler Scott A. Hahn Sonia R. Salvatore Francisco J. Schopfer Mauricio Rojas Peter Sandner Adam C. Straub Ana L. Mora |
| author_facet | Marta Bueno Jazmin Calyeca Timur Khaliullin Megan P. Miller Diana Alvarez Lorena Rosas Judith Brands Christian Baker Amro Nasser Stephanie Shulkowski August Mathien Nneoma Uzoukwu John Sembrat Brenton G. Mays Kaitlin Fiedler Scott A. Hahn Sonia R. Salvatore Francisco J. Schopfer Mauricio Rojas Peter Sandner Adam C. Straub Ana L. Mora |
| author_sort | Marta Bueno |
| collection | DOAJ |
| description | Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond. |
| first_indexed | 2024-03-11T12:06:58Z |
| format | Article |
| id | doaj.art-c430eef5b8e94876abbd6d496306422d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:58Z |
| publishDate | 2023-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c430eef5b8e94876abbd6d496306422d2023-11-07T16:25:19ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-03-0185CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signalingMarta BuenoJazmin CalyecaTimur KhaliullinMegan P. MillerDiana AlvarezLorena RosasJudith BrandsChristian BakerAmro NasserStephanie ShulkowskiAugust MathienNneoma UzoukwuJohn SembratBrenton G. MaysKaitlin FiedlerScott A. HahnSonia R. SalvatoreFrancisco J. SchopferMauricio RojasPeter SandnerAdam C. StraubAna L. MoraType II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a deadly disease with limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECIIs. Deficiency of CYB5R3 in AECIIs led to sustained activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and the sGC/cGMP/protein kinase G axis that modulates activation of the TGF-β1 signaling pathway. We demonstrate that sGC agonists (BAY 41-8543 and BAY 54-6544) are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECIIs. Taken together, these results show that CYB5R3 in AECIIs is required to maintain resilience after lung injury and fibrosis and that therapeutic manipulation of the sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.https://doi.org/10.1172/jci.insight.161487Pulmonology |
| spellingShingle | Marta Bueno Jazmin Calyeca Timur Khaliullin Megan P. Miller Diana Alvarez Lorena Rosas Judith Brands Christian Baker Amro Nasser Stephanie Shulkowski August Mathien Nneoma Uzoukwu John Sembrat Brenton G. Mays Kaitlin Fiedler Scott A. Hahn Sonia R. Salvatore Francisco J. Schopfer Mauricio Rojas Peter Sandner Adam C. Straub Ana L. Mora CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling JCI Insight Pulmonology |
| title | CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling |
| title_full | CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling |
| title_fullStr | CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling |
| title_full_unstemmed | CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling |
| title_short | CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling |
| title_sort | cyb5r3 in type ii alveolar epithelial cells protects against lung fibrosis by suppressing tgf β1 signaling |
| topic | Pulmonology |
| url | https://doi.org/10.1172/jci.insight.161487 |
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