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Activation of leukotriene B4 receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils

Cellular & Molecular Immunology volume 21, pages 245–259 (2024)Cite this article

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Abstract

Invasive fungal infections are life-threatening, and neutrophils are vital cells of the innate immune system that defend against them. The role of LTA4H-LTB4-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood. Here, we demonstrated that the LTA4H-LTB4-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus, but not Cryptococcus neoformans infection, by regulating the antifungal activity of neutrophils. Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils. Moreover, defective activation of the spleen tyrosine kinase (Syk) and extracellular signal-related kinase (ERK1/2) pathways in neutrophils accompanies this impairment. Mechanistically, BLT1 regulates CR3-mediated, β-1,3-glucan-induced neutrophil phagocytosis, while a physical interaction with CR3 with slight influence on its dynamics is observed. Our findings thus demonstrate that the LTA4H-LTB4-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.

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Acknowledgements

We thank Jingren Zhang (Tsinghua University) for providing Itgam−/−, Fcgr2b/3/4−/− mice and bacterial strains, and Guanghua Huang (Fudan University) for sharing C. albicans reporter strain. This work was partially supported by the National Key Research and Development Program of China (2019YFA0508502 to XL), National Natural Science Foundation of China (31930039, 31821003, 91942303 to XL), the General Financial Grant from the China Postdoctoral Science Foundation (2020M670301 to YX), and annual funding from Tsinghua University-Peking University Jointed Center for Life Sciences.

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  1. These authors contributed equally: Yan Xin, Sihan Xiong.

Authors and Affiliations

  1. Institute for Immunology and School of Medicine, Tsinghua University, 100084, Beijing, China

    Yan Xin, Sihan Xiong & Xin Lin

  2. Tsinghua University-Peking University Center for Life Sciences, 100084, Beijing, China

    Yan Xin & Xin Lin

  3. Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Linghong Zhou

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YX and XL conceived and designed this study. YX and SX performed experiments, data analysis, and prepared manuscript. LZ provided the scientific and clinical view for this study. All authors contributed to edit the manuscript and agree to be accountable for all aspects of the work.

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Xin, Y., Xiong, S., Zhou, L. et al. Activation of leukotriene B4 receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils. Cell Mol Immunol 21, 245–259 (2024). https://doi.org/10.1038/s41423-024-01130-4

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