Mechanosensing regulates pDC activation in the skin through NRF2 activation

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.