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A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis

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Abstract

Objective

Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood.

Methods

Experimental fungal keratitis was established in wild-type and gene knockout (TLR4−/− and GSDMD−/−) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research.

Results

Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas.

Conclusions

The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.

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Availability of data and materials

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

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (81970772 and 21906179), the National Key Research and Development Program of China (2020YFA0907500), the K.C. Wong Education Foundation of China (GJTD-2020-03), the Tianjin Natural Science Foundation (21JCZDJC01250), the Science and Technology Program of Baoding of Huifang Lian (No. 2141ZF086), and the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-016A).

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Authors and Affiliations

  1. School of Medicine, Nankai University, Tianjin, China

    Xiaolong Fang & Xiaoyong Yuan

  2. Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China

    Xiaolong Fang, Huifang Lian & Xiaoyong Yuan

  3. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China

    Xiaolong Fang, Huifang Lian, Shuang Liu, Jingcun Dong & Chunyang Liao

  4. Department of Ophthalmology, Baoding First Central Hospital, Baoding, Hebei, China

    Huifang Lian

  5. University of Chinese Academy of Sciences, Beijing, China

    Shuang Liu, Jingcun Dong & Chunyang Liao

  6. Aier Eye Hospital, Tianjin, China

    Xia Hua

  7. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    Wenguang Li

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  1. Xiaolong Fang
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Contributions

XF was involved in investigation, methodology, writing––original draft, and writing––review and editing. HL, SL, JD, and WL contributed to investigation and methodology. XH performed writing––original draft, writing––review and editing, and supervision. CYL and XYY were involved in investigation, methodology, writing––original draft, writing––review and editing, and supervision. All the authors contributed to the revision of the final manuscript.

Corresponding authors

Correspondence to Chunyang Liao or Xiaoyong Yuan.

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All animal experiments were in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and this study was formally reviewed and approved by the Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences Animal Care and Ethics Committee (Approval No. AEWC-RCEES-2022042).

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Fang, X., Lian, H., Liu, S. et al. A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis. Inflamm. Res. 72, 1485–1500 (2023). https://doi.org/10.1007/s00011-023-01757-5

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