Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease

Ye Gan, Ronald Reilkoff, Xueyan Peng, Thomas Russell, Qingsheng Chen, Susan K. Mathai, Robert Homer, Mridu Gulati, Jonathan Siner, Jack Elias, Richard Bucala, Erica Herzog

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Objective Semaphorin 7a regulates transforming growth factor β1 (TGFβ1)-induced fibrosis. This study was undertaken to test the hypothesis that semaphorin 7a exerts its profibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes. Methods A murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGFβ1 gene is overexpressed in the lung was used. Fibrosis and fibrocytes were evaluated in TGFβ1-transgenic mice in which the semaphorin 7a locus had been disrupted. The effect of replacement or deletion of semaphorin 7a on bone marrow-derived cells was ascertained using bone marrow transplantation. The role of the semaphorin 7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD). Results The appearance of fibrocytes in the lungs of TGFβ1-transgenic mice required semaphorin 7a. Replacement of semaphorin 7a on bone marrow-derived cells restored lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduced pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells (PBMCs) from patients with scleroderma-related ILD showed increased levels of messenger RNA for semaphorin 7a and its receptors, with semaphorin 7a located on collagen-producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth was enhanced in these patients. Stimulation of normal human PBMCs with recombinant semaphorin 7a enhanced fibrocyte differentiation; these effects were attenuated by β1 integrin neutralization. Conclusion Our findings indicate that interventions that reduce semaphorin 7a expression or prevent the semaphorin 7a-β1 integrin interaction may ameliorate TGFβ1-driven or fibrocyte-associated autoimmune fibroses.

Original languageEnglish (US)
Pages (from-to)2484-2494
Number of pages11
JournalArthritis and Rheumatism
Volume63
Issue number8
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

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    Gan, Y., Reilkoff, R., Peng, X., Russell, T., Chen, Q., Mathai, S. K., Homer, R., Gulati, M., Siner, J., Elias, J., Bucala, R., & Herzog, E. (2011). Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease. Arthritis and Rheumatism, 63(8), 2484-2494. https://doi.org/10.1002/art.30386