Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that has significant mortality and morbidity secondary to internal and cutaneous fibrosis. Though the exact pathogenesis remains poorly understood, fibroblast and myofibroblast activation are thought to be key contributors to the fibrotic process. Dendritic cells (DCs) can modulate mesenchymal cell activity in lymph nodes, and we hypothesized that they may also have a role in modulating the fibroblasts activity in skin fibrosis.
Methods: We induced fibrosis by injecting bleomycin (BLM, 20µg) subcutaneously into 3 adjacent points on shaved back skin for 17 or 28 days. After sacrifice, we took 3x 8mm biopsy punches of affected tissue for histology, flow cytometry and RNA extraction. Primary fibroblasts were derived from wild type, untreated mouse ears and used at passage 1. Bone marrow-derived DCs (BMDCs) were isolated from wild type, untreated bone marrow cultured in the presence of GM-CSF.
Results: By immunohistochemistry, we observe the association of CD11chi cells and alpha-smooth muscle actin+ (SMA+) myofibroblasts after BLM treatment. Using CD11c-DTR transgenic mice that allow for inducible depletion of CD11c+ cells, we depleted CD11chi cells after 15 days of BLM treatment. CD11chi cell depletion resulted in disappearance of SMA+ cells and over 2-fold decrease in TGFb1 transcription in total skin, suggesting that dendritic cells are required to maintain myofibroblasts and TGFb1 levels in fibrotic skin. Culturing BMDCs with primary fibroblasts resulted in increased SMA+ and SMA– fibroblast numbers, as well as increased SMA expression in SMA+cells, suggesting that dendritic cells are sufficient to promote fibroblast and myofibroblast proliferation and activation.
Conclusion: These results suggest a scenario whereby dendritic cells in fibrotic skin contribute to fibrosis in part by promoting the proliferation and activation of fibroblasts and myofibroblasts, perhaps via their expression of TGFb1.
J. J. Chia,
T. T. Lu,
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/cd11c-cells-are-necessary-for-myofibroblast-maintenance-in-bleomycin-induced-cutaneous-fibrosis/