2. Academic Validation
  3. Lipid asymmetry disruption by XKR8 orchestrates neutrophil extracellular trap formation and inhibits fungal infection

Lipid asymmetry disruption by XKR8 orchestrates neutrophil extracellular trap formation and inhibits fungal infection

  • Nat Immunol. 2026 May;27(5):949-960. doi: 10.1038/s41590-026-02456-z.
Weixiang Liu # 1 2,  Jieming Ping # 1 2,  Lishan Deng # 3,  Ke Wang 1 4,  Jinnuo Xu 1,  Ningxin Peng 1 5,  Mengyun Yang 1 2,  Hesen Tang 6,  Zhengjie Liu 7,  Wenliang Wang 1,  Tao Li 8,  Jun Xie 5,  Yunyun Han 9,  Zhongjun Dong 1 10 11 12,  Wei Hu 13,  Zheng Liu 14,  Ning Wu 15 16 17 18 19 20
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, China.
  • 2 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 5 Department of Cardiology, National Cardiovascular Disease Regional Center for Anhui, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 6 School of Materials Science and Engineering, Key Laboratory of Structure and Functional Regulation of Hybrid Materials of Ministry of Education, Anhui University, Hefei, China.
  • 7 Institute of Physical Science and Information Technology, Anhui University, Hefei, China.
  • 8 Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 9 Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 10 Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, China.
  • 11 Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China.
  • 12 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province Anhui Medical University, Hefei, China.
  • 13 Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 14 Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China. [email protected].
  • 15 The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei, China. [email protected].
  • 16 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 17 Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 18 Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, China. [email protected].
  • 19 Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China. [email protected].
  • 20 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province Anhui Medical University, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 41781710 DOI: 10.1038/s41590-026-02456-z
Abstract

Neutrophil extracellular traps (NETs) constitute a vital antimicrobial defense mechanism of neutrophils, contributing to various physio-pathological processes; however, the role of plasma membrane asymmetry in this process remains unknown. Here we identify Xk-related protein 8 (XKR8), a plasma membrane phospholipid scramblase, as a pivotal regulator of NETs formation. Upon NETs induction, XKR8 is cleaved by Caspase-3, thereby disrupting plasma membrane lipid asymmetry via phospholipid scrambling. Mutation of the Caspase-3 cleavage site in XKR8 impairs NET formation. Inhibition of calcium signals before lipid scrambling abrogates NET formation, whereas blockade after scrambling does not. Cleaved XKR8 reorients plasma membrane lipids, altering membrane lipid tension and promoting CA2+ signals through mechanosensitive channels. XKR8-deficient mice exhibit compromised NET formation and impaired control of Candida albicans pulmonary Infection, showing that XKR8 is indispensable for neutrophil-driven immune responses in vivo. These findings define caspase-3-XKR8plasma membrane phospholipid scrambling as a central mechanism controlling NET formation and underscore its critical role in neutrophil-dependent Antifungal immunity.

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