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The chemerin-CMKLR1 axis in keratinocytes impairs innate host defense against cutaneous Staphylococcus aureus infection

Cellular & Molecular Immunology (2024)Cite this article

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Abstract

The skin is the most common site of Staphylococcus aureus infection, which can lead to various diseases, including invasive and life-threatening infections, through evasion of host defense. However, little is known about the host factors that facilitate the innate immune evasion of S. aureus in the skin. Chemerin, which is abundantly expressed in the skin and can be activated by proteases derived from S. aureus, has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1. Here, we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S. aureus in a mouse model of cutaneous infection, whereas chemerin overexpression, which mimics high levels of chemerin in obese individuals, exacerbates S. aureus cutaneous infection. Mechanistically, we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S. aureus-induced IL-33 expression, leading to impaired skin neutrophilia and bacterial clearance. CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S. aureus by inhibiting Akt activation in mouse keratinocytes. Thus, our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S. aureus in vivo and likely increases susceptibility to S. aureus infection in obese individuals.

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Acknowledgements

This work was supported by Shanghai Science and Technology Commission 23ZR1461500 (to RH), Key Laboratory of Medical Molecular Virology (MOE/NHC) FDMVK-2021001 (to RH), The National Natural Science Foundation of China Grant 82271138 (to HL) and National Key Research and Development Program of China 2020YFC2005003 (to JC).

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  1. These authors contributed equally: Yu Chen, Yan Song, Zhe Wang.

Authors and Affiliations

  1. Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE/NHC), School of Basic Medical Sciences, and Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China

    Yu Chen, Zhe Wang, Yangfan Lai, Wei Yin, Qian Cai, Yiheng Cai, Yushan Xue & Rui He

  2. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yu Chen, Jing Chen & Rui He

  3. Department of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Yan Song & Min Li

  4. Allergy Center, Department of Otolaryngology, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, 200031, China

    Miaomiao Han & Huabin Li

  5. Department of Respiratory Diseases, Children’s Hospital of Soochow University, Suzhou, China

    Zhengrong Chen

  6. Biology Science Institutes, Chongqing Medical University, Chongqing, 400032, China

    Xi Li

  7. Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Jing Chen

  8. Faculty of Medical Laboratory Science, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China

    Min Li

  9. Research Center of Allergy and Diseases, Fudan University, 200040, Shanghai, China

    Rui He

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Contributions

RH and HL designed the experiments. YC, YS, ZW, YL, WY, QC, MH, YC and YX conducted the experiments. YC, YS, ZW and YL analyzed the data. ZC, ML, JC and LX provided essential research materials and mouse lines for the study. RH and HL supervised the study. RH, YC and YS wrote the paper.

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Correspondence to Huabin Li or Rui He.

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Chen, Y., Song, Y., Wang, Z. et al. The chemerin-CMKLR1 axis in keratinocytes impairs innate host defense against cutaneous Staphylococcus aureus infection. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01152-y

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