2. Academic Validation
  3. Postantibiotic leukocyte enhancement-mediated reduction of intracellular bacteria by macrophages

Postantibiotic leukocyte enhancement-mediated reduction of intracellular bacteria by macrophages

  • J Adv Res. 2023 Jun 6;S2090-1232(23)00148-0. doi: 10.1016/j.jare.2023.05.010.
Yifan Wu 1,  Xiaoxia Gong 1,  Jianzhong Shen 2,  Kui Zhu 3
Affiliations

Affiliations

  • 1 National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 2 National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
  • 3 National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China. Electronic address: zhuk@cau.edu.cn.
PMID: 37290606 DOI: 10.1016/j.jare.2023.05.010
Abstract

Introduction: Potentiation of the bactericidal activities of leukocytes, including macrophages, upon Antibacterial agent administration has been observed for several decades and is summarized as the postantibiotic leukocyte enhancement (PALE) theory. Antibiotics-induced Bacterial sensitization to leukocytes is commonly recognized as the mechanism of PALE. However, the degree of sensitization drastically varies with Antibiotic classes, and little is known about whether and how the potentiation of leukocytes contributes to PALE.

Objectives: In this study, we aim to develop a mechanistic understanding of PALE by investigating the immunoregulation of traditional Antibiotics on macrophages.

Methods: Interaction models between bacteria and macrophages were constructed to identify the effects of different Antibiotics on the bactericidal activities of macrophages. Oxygen consumption rate, expression of oxidases, and Antioxidants were then measured to evaluate the effects of fluoroquinolones (FQs) on the oxidative stress of macrophages. Furthermore, the modulation in endoplasmic reticulum stress and inflammation upon Antibiotic treatment was detected to analyze the mechanisms. At last, the peritoneal Infection model was utilized to verify the PALE in vivo.

Results: Enrofloxacin significantly reduced the intracellular burden of diverse Bacterial pathogens through promoting the accumulation of Reactive Oxygen Species (ROS). The upregulated oxidative response accordingly reprograms the electron transport chain with decreased production of antioxidant Enzymes to reduce internalized pathogens. Additionally, enrofloxacin modulated the expression and spatiotemporal localization of myeloperoxidase (MPO) to facilitate ROS accumulation to target invaded bacteria and downregulated inflammatory response to alleviate cellular injury.

Conclusion: Our findings demonstrate the crucial role of leukocytes in PALE, shedding light on the development of new host-directed Antibacterial therapies and the design of rational dosage regimens.

Keywords

Fluoroquinolones; Macrophage; PALE; ROS.

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