Plasmacytoid dendritic cells contribute to pro-inflammatory and pro-fibrotic milieu in lung fibrosis

Abstract

Abstract Fibrosis, the end-result of tissue injury in a wide range of diseases, contributes to >40% of mortality in the US. Plasmacytoid dendritic cells (pDC) are reduced in the peripheral blood, but increase in the lungs and skin of patients with systemic sclerosis, a prototypic fibrotic disease (JCI Insight 2018). The frequency of pDCs in the lungs of patients correlated with the severity of lung disease and with levels of proteins implicated in inflammation and fibrosis. Importantly, depletion of pDCs ameliorated lung and skin fibrosis in the bleomycin-induced animal model. pDC depletion also altered the expression levels of proteins and genes implicated in chemotaxis, inflammation, and fibrosis in the lungs. To test if pDCs directly contribute to inflammatory/profibrotic milieu in fibrosis, we injected C57Bl/6 mice with bleomycin, harvested lungs, and analyzed lungs for proteins by Western blot, ELISA, and flow cytometry. CD36 that is implicated in platelet-collagen adhesion, oxidative stress and inflammation was increased on pDCs but not on mDCs, other myeloid cells, B cells and T cells in the lungs of bleomycin-injected mice as compared to control mice. TLR7 was also increased more on pDCs than on all other immune cells examined, whereas TLR2 was increased more on mDCs and other myeloid cells but not on pDCs and B cells. TGFβ-latent peptide was higher on all immune cells examined in the lungs of bleomycin-injected animals than in controls. Among chemokine receptors, CCR2, CCR3, CCR6, CCR9 and CXCR4 were higher on pDCs than other cells. In summary, pDCs elicit profibrotic milieu in the development of systemic fibrosis. These observations identify the increased trafficking of pDCs’ to the affected organs as a therapeutic target in fibrosis.