Role of dendritic cell-derived amphiregulin in pulmonary fibrosis (CCR5P.203)

Abstract

Abstract Recruitment of dendritic cells (DCs) has been implicated in lung fibrosis. Accumulation of BM-derived DC (BMDC) was shown to play an important role in bleomycin (BLM)-induced fibrotic lungs. A microarray analysis of lung DCs derived from control and BLM-treated mice revealed amphiregulin (AREG), an epidermal growth factor receptor ligand was highly upregulated in cells from fibrotic lung. Moreover BLM-induced fibrosis and AREG induction were attenuated when BMDCs were depleted. Thus AREG induced primarily in BMDCs appear to play a significant role in this model of fibrosis. To further confirm the in vivo importance of AREG fibrosis was induced in wild type or AREG knockout (KO) mice by injecting BLM endotracheally, and the fibrotic response was analyzed biochemically and histologically. The results showed that BLM induced significant induction of HYP in WT mice was significantly decreased in AREG KO mice. The fibrotic markers collagen I and α-smooth muscle actin expressions were also significantly reduced compared to the WT mice, along with impaired proinflammatory cytokine/chemokine expression. These fibrotic responses were also reflected by tissue histopathology. Finally, unlike BMDCs isolated from wild type mice, those from AREG KO mice lacked the ability to induce myofibroblast differentiation when co-cultured with lung fibroblasts. Thus BMDC-derived AREG played an important role in pulmonary fibrosis probably by promoting fibroblast proliferation and survival.