Academic Journal
Mechanosensing regulates pDC activation in the skin through NRF2 activation.
| العنوان: | Mechanosensing regulates pDC activation in the skin through NRF2 activation. |
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| المؤلفون: | Chaudhary, Vidyanath, Mishra, Bikash, Ah Kioon, Marie Dominique, Du, Yong, Ivashkiv, Lionel B, Crow, Mary K, Barrat, Franck J |
| المصدر: | J Exp Med ; ISSN:1540-9538 ; Volume:222 ; Issue:3 |
| بيانات النشر: | Silverchair Information Systems |
| سنة النشر: | 2025 |
| المجموعة: | PubMed Central (PMC) |
| الوصف: | Plasmacytoid DCs (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I), and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://doi.org/10.1084/jem.20240852; https://pubmed.ncbi.nlm.nih.gov/39670996; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639951/ |
| DOI: | 10.1084/jem.20240852 |
| الاتاحة: | https://doi.org/10.1084/jem.20240852 https://pubmed.ncbi.nlm.nih.gov/39670996 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639951/ |
| Rights: | © 2024 Chaudhary et al. |
| رقم الانضمام: | edsbas.90F35CA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1084/jem.20240852 |
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