Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

Abstract

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

Syndecans in Inflammation at a Glance

“…Cardiac disease models showed that syndecan-1 mediates fibrosis resulting from an enhanced deposition of collagen (60,61). Similar observations were made in the lung where syndecan-4 plays an important role in limiting lung fibrosis during inflammation (62,63). ECM remodeling contributes significantly to the mechanical properties of the matrix.…”

The Influence of Polysaccharides‐Based Material on Macrophage Phenotypes

“…Syndecan‐4 heparan sulfate acts as a co‐receptor for several mediators (i.e., FGF‐2) through its heparan sulfate sidechain and is known to enhance the activity of FGF‐2 therapy. [ 19,170 ] It has been shown that an absence of syndecan‐4 delays dermal wound closure in C57BL/6 mice. [ 171 ] Similarly, human patients with venous leg ulcers had less syndecan‐4 compared to healthy skin.…”

“…[ 10,16,17 ] In general, M2 macrophages stimulate Th2 cells, relieve inflammation, and promote tissue regeneration, angiogenesis, vascularization, and tumor progression. Secretion of CCL18 9 and TGF‐ β [ 18,19 ] stimulates fibroblast proliferation/differentiation and collagen synthesis, which are crucial in the wound healing process. As a consequence of the dysregulation of the M2 phenotype, increased expression of pro‐fibrotic cytokines can also provoke fibrosis, which may negatively influence the function of the implant.…”

Potential therapeutic manipulations of the CXCR3 chemokine axis for the treatment of inflammatory fibrosing diseases

“…CXCR3 mRNA, but not protein, was detected in lung fibroblasts. Rather, direct interaction of the heparin-binding domain of CXCL10 and syndecan-4 on the lung interstitial compartment inhibits fibroblast recruitment, TGFβ signaling and subsequent fibrosis 67 , 68 . Similar findings were reported in myocardium, which required CXCL10 fibroblast responses through proteoglycans 69 , and urethral fibrosis, in which CXCL10 signaling interfered with profibrotic TGFβ signaling 70 .…”