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IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons

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Abstract

Accumulating evidences suggest that M2 macrophages are involved with repair processes in the nervous system. However, whether M2 macrophages can promote axon regeneration by directly stimulating axons nor its precise molecular mechanism remains elusive. Here, the current study demonstrated that typical M2 macrophages, which were generated by IL4 simulation, had the capacity to stimulate axonal growth by their direct effect on axons and that the graft of IL4 stimulated macrophages into the region of Wallerian degeneration enhanced axon regeneration and improved functional recovery after PNI. Importantly, uPA (urokinase plasminogen activator)-uPA receptor (uPAR) was identified as the central axis underlying the axon regeneration effect of IL4 stimulated macrophages. IL4 stimulated macrophages secreted uPA, and its inhibition abolished their axon regeneration effect. Injured but not intact axons expressed uPAR to be sensitive to uPA. These results unveil a cellular and molecular mechanism underlying the macrophage related axon regeneration and provide a basis of a novel therapy for PNI.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank M. Endo for their assistance with immunohistochemistry. We are thankful to the National BioResource Project-Rat for providing LEWTg (CAG-EGFP) rats, the Genome Information Research Center for providing Sprague Dawley-Tg (CAG-EGFP) rats, and the Open Facility, Hokkaido University Sousei Hall for access to the cryostat.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (17K11527), the Japan Agency for Medical Research and Development (JP20gm6210004), the General Insurance Association of Japan (2017–2020), the Kobayashi Foundation, and the SEI Group CSR Foundation.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan

    Yuki Matsui, Ken Kadoya, Takeshi Endo, Masato Hara, Gen Matsumae, Tomoaki Suzuki, Yasuhiro Yamamoto, Mohamad Alaa Terkawi & Norimasa Iwasaki

  2. Department of Orthopaedic Surgery, National Hospital Organization, Hokkaido Medical Center, Sapporo, Japan

    Yusuke Nagano

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  1. Yuki Matsui
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  2. Ken Kadoya
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Contributions

Conceptualization: YM and KK. Methodology: YM, KK and AT. Investigation: YM, KK, YN, MH, GM, TS, YY and AT. Funding acquisition: KK and NI. Project administration: KK and NI. Supervision: KK and NI. Writing—original draft: YM and KK.

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Correspondence to Ken Kadoya.

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All experimental procedures involving animals were approved by the local ethical committee of the Hokkaido University.

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18_2022_4310_MOESM1_ESM.jpg

Suppl. Fig. 1: Gait analysis of the graft of IL-4Mφ after PNI The gait analysis was performed at pre-injury, and at 4 and 8 weeks after the crush injuries using DigiGait. No statistical difference was detected between the rats injected with the IL-4Mφ graft and the control rats in most of the gait parameters except paw drag and swing duration at 8 weeks after injury. *P < 0.05 vs. PBS injection. Student’s t test was used for analysis. N = 10 per group. Error bars represent SEM. (JPG 150 KB)

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Matsui, Y., Kadoya, K., Nagano, Y. et al. IL4 stimulated macrophages promote axon regeneration after peripheral nerve injury by secreting uPA to stimulate uPAR upregulated in injured axons. Cell. Mol. Life Sci. 79, 289 (2022). https://doi.org/10.1007/s00018-022-04310-5

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