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JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression

Nature Medicine volume 23, pages 337–346 (2017)Cite this article

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Abstract

Opportunistic fungal infections are a leading cause of death among immune-compromised patients, and there is a pressing need to develop new antifungal therapeutic agents because of toxicity and resistance to the antifungal drugs currently in use. Although C-type lectin receptor– and Toll-like receptor–induced signaling pathways are key activators of host antifungal immunity, little is known about the mechanisms that negatively regulate host immune responses to a fungal infection. Here we found that JNK1 activation suppresses antifungal immunity in mice. We showed that JNK1-deficient mice had a significantly higher survival rate than wild-type control mice in response to Candida albicans infection, and the expression of JNK1 in hematopoietic innate immune cells was critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 gene promoter. Blocking either CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced antifungal response found in JNK1-deficient mice. Notably, JNK inhibitors exerted potent antifungal therapeutic effects in both mouse and human cells infected with C. albicans, indicating that JNK1 may be a therapeutic target for treating fungal infection.

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Figure 1: JNK1 negatively regulates the antifungal innate immune response.
Figure 2: JNK1 suppresses CD23 induction by C. albicans.
Figure 3: Elevated CD23 and iNOS expression in JNK1 KO mice is responsible for the enhanced antifungal immune response.
Figure 4: JNK1 negatively regulates CD23 expression through elevated dectin-1-dependent NFAT activation.
Figure 5: JNK inhibitor shows therapeutic effect in antifungal immunity in vivo.
Figure 6: JNK inhibitor promotes the antifungal response in human cells.

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Acknowledgements

We thank X. Hu, Y. Shang and L. Ni for helpful discussion. We thank X. Xu, L. Mu, S. Xie and T. Xia for technical assistance. We thank D.C. Lin for editing the English in this manuscript. This work was partially supported by grants from the National Natural Science Foundation of China (81502460 and 31670904 to X.Z., 91542107 and 81630058 to X.L., 81571611 to X.J.) and National Institutes of Health (AI116722 to X.L.).

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Author notes

  1. Xueqiang Zhao and Yahui Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Immunology, Tsinghua University School of Medicine, Beijing, China

    Xueqiang Zhao, Yahui Guo, Qing Chang, Tianming Luo, Bin Zhang, Chen Dong & Xin Lin

  2. Departments of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Changying Jiang, Mien-Chie Hung & Xin Lin

  3. Department of Immunology, Tongji University School of Medicine, Shanghai, China

    Shilei Zhang & Xinming Jia

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  1. Xueqiang Zhao
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Contributions

X.Z. and Y.G. performed most of the experiments. C.J. and T.L. performed some of the mouse experiments. Q.C. and S.Z. performed some of the in vitro experiments. B.Z. analyzed the RNA–seq data and helped prepare the figures. X.J., M.-C.H. and C.D. provided key reagents and insightful discussion. X.L. and X.Z. conceived the project and wrote the manuscript.

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Correspondence to Xueqiang Zhao or Xin Lin.

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Zhao, X., Guo, Y., Jiang, C. et al. JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression. Nat Med 23, 337–346 (2017). https://doi.org/10.1038/nm.4260

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