Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

Abstract

Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4 -/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4 -/-mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.

Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis

“…Primary fibroblasts were derived from mouse lungs as described previously (66). The mouse primary fibroblasts were used from 3 to 6 passages.…”

“…The mouse primary fibroblasts were used from 3 to 6 passages. Human lung fibroblasts were isolated from lung transplant explants obtained from patients with IPF as described previously (35,66,67). All cases fulfilled multidisciplinary diagnostic criteria described in the American Thoracic Society/Euro pean Respiratory Society consensus statement.…”

Pulmonary fibrosis: patterns and perpetrators

“…Both populations are capable of releasing a variety of mediators that have chemotactic properties for fibroblasts (54)(55)(56), but the relative contributions of these cell types has been difficult to discern. Recently, lysophosphatidic acid (LPA) has been shown to be present following lung injury, and its cognate receptor, LPAR1, is necessary for the recruitment of fibroblasts to the lung and the development of fibrosis following lung injury (55).…”

Up-Regulation of Heparan Sulfate 6-O-Sulfation in Idiopathic Pulmonary Fibrosis

“…TGF-b1 induces syndecan-2 expression in primary human lung fibroblasts (17). Syndecan-4 expression is up-regulated in bleomycin-induced lung injury, and syndecan-4 null mice exhibit a dysregulated inflammatory response, increased myofibroblast recruitment, and interstitial fibrosis after bleomycin administration (18). In addition to alterations in the syndecan core proteins, heparan sulfate (HS) is increased in radiation-induced lung injury and in bleomycin-induced lung fibrosis in mice (19,20).…”