2024/11/28 by Vidyanath Chaudhary, Bikash Mishra, Marie Dominique Ah Kioon +4 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #Skin and Cellular Biology Research #Systemic Sclerosis and Related Diseases #T-cell and B-cell Immunology
paper · doi:10.1084/jem.20240852
openalex publication_date 2024/11/28 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
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.