Background/Purpose:

Dipeptidyl-peptidase-4 (DPP4) has been reported to identify a dermal fibroblast lineage involved in scaring and its inhibition leads to reduced scar formation. Its role in tissue fibrosis, however, is unknown. The aim of the study was to characterize DPP4 positive cells and their mechanism of action and to evaluate the antifibrotic effect of DPP4 inhibition in different preclinical models of systemic sclerosis (SSc).

Methods: Expression of DPP4 in human and murine skin was analyzed by immunofluorescence and Western blot. Mouse fibroblasts were isolated and DPP4 positive cells properties were assessed. Two DPP4 inhibitors were tested in two concentrations administered oral in bleomycin-induced skin fibrosis and in sclerodermatous chronic graft-versus-host disease (scl-cGvHD) model. Pulmonary and dermal fibrosis was induced by bleomycin in DPP4 knockout (KO) mice and wildtype littermates. The antifibrotic effects were assessed by hydroxyproline assay, quantification of myofibroblasts and analyses of the dermal thickness. Fibrosis of the lungs was additionally evaluated by computer tomography scans (CT). Inflammatory infiltrates were assessed by CD45 staining.

Results: DPP4 positive fibroblasts were increased in fibrotic skin of SSc patients and also in murine models of fibrosis. DPP4 expression is induced by TGF-β in an Erk-dependent manner. DPP4-expressing fibroblasts were activated and strongly expressed alpha smooth muscle actin (SMA) and stress fibers after TGF-β stimulation. These cells also released increased amounts of collagen. Furthermore, DPP4-positive fibroblasts showed a higher proliferation rate and an increased migratory capacity. Pharmacological inhibition of DPP4 reduced the release of collagen and the expression of myofibroblast markers. DPP4-KO mice are less sensitive to bleomycin-induced pulmonary fibrosis as shown by milder changes on CT, reduced Ashcroft scores and reduced hydroxyproline content. DPP4-KO mice also show reduced skin fibrosis upon bleomycin challenge. Moreover, treatment with DPP4 inhibitors in pharmacologically relevant and well tolerated doses demonstrated potent antifibrotic effects in bleomycin-induced skin fibrosis and experimental scl-cGvHD mouse model with reduced dermal thickening, decreased collagen deposition and reduced myofibroblast counts. Treatment with DDP4 inhibitors also reduced leukocyte infiltrations into the skin. No anti-fibrotic effects of DPP4 inhibition were observed in DPP4-KO mice, confirming that the antifibrotic effects of DPP4 inhibitors are not mediated by off-target effects. Mechanistically, inhibition of DPP4 selectively interferes with the TGF-β induced activation of ERK signaling, but does not inhibit TGF-β induced SMAD signaling, or other non-canonical TGF-β pathways involving Fra2, c-Jun, p38, Akt or STAT3.

Conclusion: DPP4 characterizes an activated subpopulation of fibroblasts in SSc. However, DPP4 does not only serve as an activation marker, but is also functionally required for fibroblast activation and tissue fibrosis. These results may have direct translational implications as DPP4 inhibitors are already in clinical use for diabetes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dipeptidyl-peptidase-4-dpp4-promotes-fibroblast-activation-and-is-a-potential-molecular-target-for-treatment-of-fibrosis/