TNF-α-stimulated fibroblasts secrete lumican to promote fibrocyte differentiation.

Abstract

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-α 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. α2β1, αMβ2, and αXβ2 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.

• Authors: Darrell Pilling, Varsha Vakil, Nehemiah Cox, Richard H Gomer
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 38 Pg. 11929-34 (Sep 22 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26351669 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Blocking
• Chondroitin Sulfate Proteoglycans
• Culture Media, Conditioned
• Decorin
• Integrin alpha2
• Intercellular Signaling Peptides and Proteins
• LUM protein, human
• Lumican
• Nerve Tissue Proteins
• Peptides
• Tumor Necrosis Factor-alpha
• Bleomycin
• Keratan Sulfate
• Trypsin
• Slit homolog 2 protein

Topics

• Animals
• Antibodies, Blocking (metabolism)
• Bleomycin
• Cell Differentiation (drug effects)
• Cell Polarity (drug effects)
• Chemical Fractionation
• Chondroitin Sulfate Proteoglycans (metabolism)
• Culture Media, Conditioned (pharmacology)
• Decorin (metabolism)
• Disease Models, Animal
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Integrin alpha2 (metabolism)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Keratan Sulfate (metabolism)
• Lumican
• Lung (drug effects, metabolism, pathology)
• Macrophages (cytology, drug effects)
• Nerve Tissue Proteins (metabolism)
• Peptides (metabolism)
• Pulmonary Fibrosis (metabolism, pathology)
• Trypsin (metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)