期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：38
页码：11929-11934
DOI：10.1073/pnas.1507387112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceFibrosis is involved in 30-45% of deaths in the U.S. The disease may involve a runaway positive feedback loop between fibroblasts and monocyte-derived fibrocytes. The signals from fibrocytes to fibroblasts include inflammatory cytokines such as TNF-, but the signals from TNF--stimulated fibroblasts to fibrocytes are unknown. We find that one of these signals is the protein lumican, and show that lumican levels are increased in fibrotic lesions. The identification of lumican as a signal in fibrotic tissues that promotes fibrocyte differentiation represents a major advance in our understanding of the regulation of the innate immune system, supports the positive feedback loop model of fibrosis, and indicates that lumican-inhibiting drugs may be beneficial in regulating fibrosis. In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called fibrocytes help to form scar tissue. Although fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to fibrocytes. In this report, we show that fibroblasts stimulated with the fibrocyte-secreted inflammatory signal tumor necrosis factor- secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human fibrocyte differentiation. Lumican competes with the serum fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. 2{beta}1, M{beta}2, and X{beta}2 integrins are needed for lumican-induced fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.
