Toll-Like Receptor 8 is Expressed in Monocytes in Contrast to Plasmacytoid Dendritic Cells and Mediates Aberrant Interleukin-10 Responses in Patients With Systemic Sclerosis.

Abstract

Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll-like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc. Monocytes, conventional dendritic cells (cDCs), and pDCs from the blood and skin of patients with SSc were analyzed for TLR8 protein expression. To assess TLR function, cytokine responses upon TLR7 and TLR8 stimulation were studied. To identify relevant alterations specific for patients with SSc (n = 16), patients with primary Sjögren disease (pSS; n = 10) and healthy controls (HCs; n = 13) were included into the study. In all individuals, TLR8 was expressed in monocytes and cDCs but not in pDCs. The TLR8 expression levels were overall similar in patients with SSc and pSS and HCs. Additionally, in all study participants, TLR8 stimulation of pDCs did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin (IL)-10 responses upon TLR8 (patients with SSc vs HCs, P = 0.0126) and TLR7/8 stimulation (patients with SSc vs HCs, P = 0.0170). TLR8 protein is not expressed in pDCs of patients with SSc. Accordingly, they do not respond to TLR8 stimulation. In contrast, monocytes of patients with SSc respond to TLR8 stimulation with increased IL-10 responses. Therefore, TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression.