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S100A12 inhibits fibroblast migration via the receptor for advanced glycation end products and p38 MAPK signaling

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Abstract

The migration of lung fibroblasts plays a pivotal role in wound repair and fibrotic processes in the lung. Although the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of lung diseases, its role in lung fibroblast migration is unclear. The current study examined the effect of three different RAGE ligands, namely, high mobility group box 1 (HMGB1), S100A12, and N-epsilon-(carboxymethyl) lysine (CML), on human fibronectin-directed human fetal lung fibroblast (HFL-1) migration. HMGB1 augmented, whereas S100A12 inhibited, HFL-1 migration in a concentration-dependent manner. CML did not affect HFL-1 migration. The effect of HMGB1 was not through RAGE. However, the effect of S100A12 was mediated by RAGE, but not Toll-like receptor 4. S100A12 did not exert a chemoattractant effect, but inhibited HFL-1 chemotaxis and/or chemokinesis. Moreover, S100A12 mediated HFL-1 migration through p38 mitogen-activated protein kinase (MAPK) but not through nuclear factor-kappa B, protein kinase A, phosphatase and tensin homolog deleted on chromosome 10, or cyclooxygenase. In addition, western blot analysis showed that S100A12 augmented p38 MAPK activity in the presence of human fibronectin. In conclusion, S100A12 inhibits lung fibroblast migration via RAGE-p38 MAPK signaling. This pathway could represent a therapeutic target for pulmonary conditions characterized by abnormal tissue repair and remodeling.

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Acknowledgments

The authors would like to thank Dr. Takayuki Jujo, Ms. Tomoko Misawa, Ms. Ikuko Sakamoto, and Ms. Akiko Moriya for the experimental assistance, and Ms. Chieko Handa, Ms. Tamie Hirano, and Ms. Mika Sakurai for the secretarial assistance.

Funding

This research was supported by grants from JSPS KAKENHI (grant number 17K09646) and GSK Japan Research Grant 2016 (grant number A-35).

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Authors and Affiliations

  1. Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo Ward, Chiba City, 260-8670, Japan

    Nozomi Tanaka, Jun Ikari, Rie Anazawa, Masaki Suzuki, Yusuke Katsumata, Ayako Shimada, Eiko Suzuki, Yukiko Matsuura, Naoko Kawata, Yuji Tada & Koichiro Tatsumi

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  1. Nozomi Tanaka
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Correspondence to Jun Ikari.

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Editor: Tetsuji Okamoto

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Tanaka, N., Ikari, J., Anazawa, R. et al. S100A12 inhibits fibroblast migration via the receptor for advanced glycation end products and p38 MAPK signaling. In Vitro Cell.Dev.Biol.-Animal 55, 656–664 (2019). https://doi.org/10.1007/s11626-019-00384-x

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