pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis

Abstract

Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis. As with animal findings, the frequency of pDCs in the lungs of patients with systemic sclerosis correlated with the severity of lung disease and with the frequency of CD4+ and IL-4+ T cells in the lung. Finally, treatment with imatinib that has been reported to reduce and/or prevent deterioration of skin and lung fibrosis profoundly reduced pDCs in lungs but not in peripheral blood of patients with systemic sclerosis. These observations suggest a role for pDCs in the pathogenesis of systemic fibrosis and identify the increased trafficking of pDCs to the affected organs as a potential therapeutic target in fibrotic diseases.

Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis

“…Two key studies have recently demonstrated the pathogenic role of pDCs in SSc pathogenesis 33 34. In line with these findings, we observed pDC infiltration to the skin when exposed to bleomycin, mimicking pDC accumulation in the skin of patients with SSc.…”

“…The role of pDCs in bleomycin model has been demonstrated recently 33 34. In line with this finding, the number of Siglec-H+ dermal pDCs was significantly increased in the skin after bleomycin treatment (figure 5A,B).…”

“…Potentially, this could contribute to the reduced levels of circulating pDCs in patients with SSc and mice with experimental SSc, possibly to lymph nodes or inflamed tissue. In patients with SSc, we and others have demonstrated increased presence of pDCs in the skin,10–13 33 34 corroborating this assumption. The role of RUNX3 in pDCs differentiation or homeostasis in vivo still needs further investigation.…”

Targeting human Plasmacytoid dendritic cells through BDCA2 prevents inflammation and fibrosis in xenotransplant mouse model of Scleroderma

“…Elevated IFN gene signature in affected organs and in the blood is a key indicator of SSc disease severity, and has been shown to precede the onset of clinical fibrosis [13]. Since pDC are known to be the key cell type for activating IFN response to virus [3,4], along with increasing evidence suggesting mouse pDC are important for disease development [10,37], we developed our study to research the role of human pDC in inflammation and fibrosis of the skin. Specifically, we set out to determine whether targeting BDCA2 could suppress the IFN response and pro-fibrotic activation of pDC and ultimately inform the rationale for pDC targeted therapy for SSc.…”

The immunopathogenesis of fibrosis in systemic sclerosis

“…The expression of genes involved in chemotaxis, dendritic cell differentiation, inflammation and fibrosis in the lungs of pDC-depleted mice was also significantly reduced. Alongside this, B and T cells were also found to be reduced in the lungs, suggesting an important role for ongoing immune abnormalities induced by DCs [119]. In another bleomycininduced pulmonary fibrosis mouse model, DC accumulation in the lung was reduced through blocking of TGF-β with the use of inhibitor SB431542 [120].…”