Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis

Abstract

Objective Expression of dipeptidylpeptidase 4 (DPP‐4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP‐4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP‐4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods Expression of DPP‐4 in skin biopsy samples and dermal fibroblasts was analyzed by real‐time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP‐4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results The expression of DPP‐4 and the number of DPP‐4–positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)–dependent manner. DPP‐4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ‐induced ERK signaling. DPP4‐knockout mice were less sensitive to bleomycin‐induced dermal and pulmonary fibrosis (P < 0.0001 versus wild‐type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft‐versus‐host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion DPP‐4 characterizes a population of activated fibroblasts and shows that DPP‐4 regulates TGFβ‐induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well‐tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.

Origin and functional heterogeneity of fibroblasts

“…In both murine and human skin, scRNA sequencing identified a DPP4 (dipeptidyl‐peptidase‐4)‐rich fibroblast population that expresses type I collagen and possibly plays a role in scarification . DPP4 transcripts and protein are also recognized as a fibroblast activation marker in systemic sclerosis . Interestingly, scRNA sequencing of dermal white adipocyte tissue reveal a subset of fibroblasts might originate from a myeloid linage .…”

Soluble Dipeptidyl Peptidase-4 Induces Fibroblast Activation Through Proteinase-Activated Receptor-2

“…DPP4 is highly expressed in bronchial epithelial cells of patients with asthma, and it increased cell proliferation in airway constitutive cells (Shiobara et al, 2016). Increased DPP4 levels were observed in fibroblasts isolated from individuals with systemic sclerosis relative to fibroblasts isolated from healthy individuals (Soare et al, 2020). Furthermore, the DPP4-positive fibroblast populations in the skin are highly proliferative and expand upon tissue injury to promote wound healing (Rinkevich et al, 2015).…”

DPP4 inhibition: Preventing SARS‐CoV‐2 infection and/or progression of COVID‐19?

“…Interestingly, in an experimental model of acute respiratory distress syndrome (ARDS), which represent the main death cause of SARS‐CoV‐2 infected patients, DPP4 inhibition by sitagliptin alleviated histological findings of lung injury by inhibiting proinflammatory cytokines IL‐1β, TNFα, and IL‐6 27 . Moreover, loss of DPP4 activity through gene knockout or treatment with sitagliptin may exert anti‐fibrotic properties in mice with bleomycin‐induced dermal or pulmonary fibrosis 28 …”