LAUSR

The production of CXCL4 and IFN-α by plasmacytoid DCs in response to TLR8 signaling contributes to skin fibrosis and systemic sclerosis. Plasmacytoid DCs foster fibrosis As potent producers of type I interferon, plasmacytoid dendritic cells (pDCs) have been implicated in multiple autoimmune disorders. Here, Ah Kioon and colleagues show that pDCs contribute to skin fibrosis in systemic sclerosis, largely through activation of TLR8, which is not normally expressed in these cells, and secretion of CXCL4. These data were garnered from systemic sclerosis patient samples and mouse models. Depletion of pDCs from mice with established fibrosis ameliorated disease symptoms, further suggesting that targeting these cells could help patients with this devastating disease. Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)–induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients.