Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Plasmacytoid Dendritic Cells (PDCs) are the key cell type mediating TLR-induced inflammation in several autoimmune diseases such as lupus, dermatomyositis, lichen sclerosus and cutaneous GVHD. In these diseases, PDC infiltrate the skin and produce IFNα, contributing to cutaneous lesions. In lupus, IFNα production was due to TLR7 and -9 recognition of endogenous RNA and DNA respectively. PDCs may also be part of the pathogenesis of systemic sclerosis (SSc). PDCs traffic to the skin in a mouse model of stiff skin syndrome. Moreover PDCs from SSc patients secrete CXCL4 and their levels in the serum correlated with skin and pulmonary disease. Although it is well described that PDC infiltrate the skin following injury or in diseases, little is known about what is controlling PDC trafficking and subsequent activation in the skin or whether PDCs can play a role in promoting/sustaining inflammation-related fibrosis. The aim of our study was to identify the nature of PDC activation in SSc patients, the role of TLRs or the impact of CXCL4 on PDC response.
For the human studies, blood was obtained from 87 SSc patients and 23 healthy volunteers (HV), and PBMCs were isolated by density gradient. PDC were then isolated from PBMC by positive selection with BDCA4 magnetic beads or by cell sorting. In mice, fibrosis was induced by sub-cutaneous injection of bleomycin (BLM) in WT and transgenic mice expressing human TLR8 (Tg8).
Results: Aberrant expression of TLR8 was observed on SSc PDCs while absent on HV. TLR8 activation in SSc PDCs significantly induced CXCL4 secretion (p=0.003) compared to unstimulated PDC while TLR9 induction had no effect (p=0.5). TLR8 activation led to an increase secretion of IFNα and pro-inflammatory IL-6 and TNF. CXCL4 further increased TLR8-induced IFNα production by PDC (3-fold) (1393±153pg/ml for TLR8-induced PDC vs 5003±747pg/ml for CXCL4+TLR8-induced PDC) while it had no effect on IL-6 (1390±129pg/ml vs 1365±100pg/ml) and TNF production (3404±241pg/ml vs 3251±207pg/ml). In mice, following BLM treatment, a significant increase in skin thickness was observed in WT mice (200±6mm vs 357±3mm, p<0.0001) and further increased in Tg8 mice (396±5mm, p=0.04 vs WT BLM). Moreover, PDCs accumulation was observed in the skin of WT BLM mice as compared to WT PBS as assessed by in situ analysis of SiglecH positive cells. PDCs infiltration were further enhanced in the skin of Tg8 mice (p=0.0008) as well as enhanced expression of IFN related genes, IP10 (p=0.006), IFIT2 and IFI35 (p=0.03).
Conclusion: Taken together our data demonstrate that the secretion of CXCL4 is due to the aberrant presence of TLR8 on PDCs of SSc patients, and that CXCL4 contributes to excessive IFNα response by TLRs. In mice, TLR8 exacerbates fibrosis due to an increased PDC infiltration in the skin.
To cite this abstract in AMA style:Ah Kioon MD, Tripodo C, Morquette A, Spiera RF, Gordon JK, Barrat FJ. Plasmacytoid Dendritic Cells Activated through TLR8 Promote Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/plasmacytoid-dendritic-cells-activated-through-tlr8-promote-systemic-sclerosis/. Accessed July 15, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasmacytoid-dendritic-cells-activated-through-tlr8-promote-systemic-sclerosis/