4.6 Article

Altered Mitochondrial Homeostasis during Systemic Lupus Erythematosus Impairs Neutrophil Extracellular Trap Formation Rendering Neutrophils Ineffective at Combating Staphylococcus aureus

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JOURNAL OF IMMUNOLOGY
卷 208, 期 2, 页码 454-463

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AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2100752

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资金

  1. National Institute of Allergy and Infectious Diseases [R01AI069233, R01AI073843, R01AI101171, R01AI153167]
  2. Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship [F32HL144081]
  3. Edward P. Evans Foundation
  4. Incyte Pharmaceuticals funds
  5. Lupus Research Alliance William Paul Distinguished Innovator Award
  6. Vanderbilt Ingram Cancer Center [P30 CA68485]
  7. Vanderbilt Digestive Disease Research Center [DK058404]
  8. National Institute of Diabetes and Digestive and Kidney Diseases Integrated Training in Engineering and Diabetes Grant [T32DK101003, R01DK105550]

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This study demonstrates that the accumulation of intracellular S100A9 in neutrophils from SLE patients is associated with impaired mitochondrial homeostasis, leading to a decrease in bactericidal activity of these neutrophils.
Inflammation involves a delicate balance between pathogen clearance and limiting host tissue damage, and perturbations in this equilibrium promote disease. Patients suffering from autoimmune diseases, such as systemic lupus erythematosus (SLE), have higher levels of serum S100A9 protein and increased risk for infection. S100A9 is highly abundant within neutrophils and modulates antimicrobial activity in response to bacterial pathogens. We reasoned that increased serum S100A9 in SLE patients reflects accumulation of S100A9 protein in neutrophils and may indicate altered neutrophil function. In this study, we demonstrate elevated S100A9 protein within neutrophils from SLE patients, and MRL/lpr mice associates with lower mitochondrial superoxide, decreased suicidal neutrophil extracellular trap formation, and increased susceptibility to Staphylococcus aureus infection. Furthermore, increasing mitochondrial superoxide production restored the antibacterial activity of MRL/lpr neutrophils in response to S. aureus. These results demonstrate that accumulation of intracellular S100A9 associates with impaired mitochondrial homeostasis, thereby rendering SLE neutrophils inherently less bactericidal.

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