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pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis
Suzanne Kafaja, … , Dinesh Khanna, Ram Raj Singh
Suzanne Kafaja, … , Dinesh Khanna, Ram Raj Singh
Published May 3, 2018
Citation Information: JCI Insight. 2018;3(9):e98380. https://doi.org/10.1172/jci.insight.98380.
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Research Article Inflammation Pulmonology

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

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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.

Authors

Suzanne Kafaja, Isela Valera, Anagha A. Divekar, Rajan Saggar, Fereidoun Abtin, Daniel E. Furst, Dinesh Khanna, Ram Raj Singh

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Figure 2

Effect of depletion of pDCs on skin and lung disease in bleomycin-injected animals.

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Effect of depletion of pDCs on skin and lung disease in bleomycin-inject...
Animals were injected with PBS or bleomycin (Bleo), and bleomycin-injected animals treated with PBS, an isotype-matched control Ab (Intact), or an anti–PDCA-1 Ab (Depleted), as described in Supplemental Figure 2A. Animals were monitored for general health and skin lesions, and organs were harvested on day 28. (A) Representative photographs illustrate clinical features, including the hunched back appearance (h), submandibular erythema (e), piloerection (p), and alopecia (a), in bleomycin-injected mice. None of the PBS-injected mice had these lesions. (B and C) Each of the aforementioned features were given a score of 1, as described in Methods, and clinical severity scores derived for individual animals (n = 9, 9, 22, and 19 animals in PBS, bleomycin alone, bleomycin + control Ab, and bleomycin + anti–PDCA-1 Ab groups, respectively). (D–F) Lung sections stained with H&E were scored for the severity of lung disease. Representative photomicrographs and histology scores are shown (magnification, 10×). (G and H) Skin sections stained with H&E were analyzed for dermal thickness, as indicated by arrows in the representative photomicrographs (magnification, 4×). Results are shown as symbol plots, each symbol representing an animal, and/or as stack plots. Horizontal lines on symbol plots represent mean values. Each stack on stack plots represents proportion of animals with a clinical or histology score, as indicated by the legend on the right of panels. *P < 0.05, **P < 0.01, ***P <0.001 (1-way ANOVA with Newman-Keuls multiple comparisons test in B, E, and H; χ2 test with Yates correction in C and F).

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