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The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury

Cellular & Molecular Immunology volume 8, pages 305–314 (2011)Cite this article

Abstract

Inflammatory stimuli, such as a microbes or lipopolysaccharides, induce a rapid release of neutrophils from the bone marrow and promote neutrophil migration into inflamed sites to promote host defense. However, an excess accumulation and retention of neutrophils in inflamed tissue can cause severe tissue injuries in the later stages of inflammation. Recent studies have reported that both CXCL12 levels in injured lungs and its receptor, CXCR4, on accumulated neutrophils in injured lungs, increased; furthermore, these studies showed that the CXCL12/CXCR4 signaling pathway participated in neutrophil accumulation in the later stages of lipopolysaccharide (LPS)-induced lung injury. However, the mechanisms underlying this increase in surface CXCR4 expression in neutrophils remain unclear. In this study, we found that surface CXCR4 expression increased in extravascular, but not intravascular, neutrophils in the lungs of LPS-induced lung injury model mice. Furthermore, ex vivo studies revealed that CXCL12 acted not only as a chemoattractant, but also as a suppressor of cell death for the lung neutrophils expressing CXCR4. Sulfatide, one of the native ligands for L-selectin, induced the increase of surface CXCR4 expression on isolated circulating neutrophils, suggesting that the activation of L-selectin may be involved in the increase in surface CXCR4. Our findings show that surface CXCR4 levels on neutrophils increase after extravasation into injured lungs, possibly through the activation of L-selectin. The CXCL12/CXCR4 signaling pathway plays an important role in the modulation of neutrophil activity during acute lung injury, not only by promoting chemotaxis but also by suppressing cell death.

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Acknowledgements

This work was supported by grants from the Japanese Society for the Promotion of Science (no. 17590776 to HK and no. 17790524 to MY). The authors declare no financial or commercial conflict of interest.

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Authors and Affiliations

  1. Department of Regional Cooperation for Infectious Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Mitsuhiro Yamada, Hiroyuki Kunishima, Masamitsu Hatta & Mitsuo Kaku

  2. Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Hiroshi Kubo, Kota Ishizawa, Mei He, Takaya Suzuki & Naoya Fujino

  3. Department of Respiratory Medicine, Japanese Red-Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan

    Seiichi Kobayashi

  4. Department of Infection Control and Laboratory Diagnostics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Katsushi Nishimaki, Tetsuji Aoyagi, Kouichi Tokuda, Miho Kitagawa & Mitsuo Kaku

  5. Department of Clinical Microbiology with Epidemiological Research & Management and Analysis of Infectious Diseases, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Hisakazu Yano

  6. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan

    Hirokazu Tamamura

  7. Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Nobutaka Fujii

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  1. Mitsuhiro Yamada
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Correspondence to Hiroshi Kubo.

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Yamada, M., Kubo, H., Kobayashi, S. et al. The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury. Cell Mol Immunol 8, 305–314 (2011). https://doi.org/10.1038/cmi.2011.8

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