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Updated: Jul 27, 2025
Bone Marrow-derived Macrophage Production
Published on: November 22, 2013
Postantibiotic leukocyte enhancement-mediated reduction of intracellular bacteria by macrophages
Yifan Wu1, Xiaoxia Gong1, Jianzhong Shen1
1National Key Laboratory of Veterinary Public Health Security, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
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.
Insights
This study reveals how fluoroquinolones enhance macrophage bactericidal activity by increasing reactive oxygen species (ROS) and modulating inflammation, crucial for postantibiotic leukocyte enhancement (PALE). This clarifies the role of leukocytes in PALE and informs new antibacterial therapies.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- The postantibiotic leukocyte enhancement (PALE) theory describes how antibiotics boost leukocyte bactericidal activity.
- While antibiotic-induced bacterial sensitization is known, the specific contribution of enhanced leukocyte function to PALE remains unclear.
- Understanding how different antibiotic classes modulate leukocyte activity is essential for optimizing antibacterial strategies.
Purpose of the Study:
- To elucidate the mechanistic basis of PALE by investigating the immunomodulatory effects of traditional antibiotics on macrophages.
- To determine how antibiotics influence macrophage bactericidal activity and oxidative stress.
- To explore the role of endoplasmic reticulum stress and inflammation in antibiotic-mediated PALE.
Main Methods:
- Macrophage-bacteria interaction models were used to assess antibiotic effects on macrophage bactericidal activity.
- Oxygen consumption, oxidase, and antioxidant levels were measured to evaluate fluoroquinolone (FQ)-induced oxidative stress in macrophages.
- Endoplasmic reticulum stress, inflammation, and in vivo peritoneal infection models were employed to analyze PALE mechanisms.
Main Results:
- Enrofloxacin enhanced macrophage killing of bacterial pathogens by increasing reactive oxygen species (ROS) accumulation.
- This oxidative response reprogrammed the electron transport chain, decreasing antioxidant enzymes and intracellular bacterial burden.
- Enrofloxacin modulated myeloperoxidase (MPO) and reduced inflammation, alleviating cellular injury.
Conclusions:
- Leukocytes play a critical role in the PALE phenomenon.
- Findings support the development of host-directed antibacterial therapies.
- The study provides insights for designing rational antibiotic dosage regimens to leverage PALE.
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