Targeted Nuclear Degranulation of Neutrophils Promotes the Progression of Pneumonia in Ulcerative Colitis

Rheumatology and Immunology Infectious Diseases Life Sciences Gastroenterology Medicine Immunology
neutrophils targeted nuclear degranulation ulcerative colitis pneumonia immune cell migration

Academic Background

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease often accompanied by various extraintestinal complications, among which pulmonary infections are particularly severe. Although previous studies have indicated interactions between the intestinal and pulmonary immune systems, the specific mechanisms involving neutrophils in this process remain unclear. Neutrophils are crucial immune cells that combat infections by releasing Neutrophil Extracellular Traps (NETs). However, excessive NETs release can lead to tissue damage, especially in pulmonary infections. Therefore, this study aims to explore how neutrophils in UC patients promote the progression of pneumonia through the Targeted Nuclear Degranulation mechanism.

Source of the Paper

This paper was co-authored by Yiming Shao, Qibing Zheng, Xiaobei Zhang, and others, with the research team from multiple departments including the Taishan Scholars Laboratory and the Department of Burns and Plastic Surgery at the Affiliated Hospital of Jining Medical University, China. The paper was published on October 14, 2024, in the journal Precision Clinical Medicine, with the DOI 10.1093/pcmedi/pbae028.

Research Process and Results

1. Neutrophil Extraction and Functional Analysis

The study first isolated neutrophils from the peripheral blood of UC patients and healthy volunteers. Using immunofluorescence, flow cytometry, and Western blot techniques, the existence of “nucleus-directed degranulation” in vitro was confirmed. The study also employed AriVis software for precise analysis and utilized a DSS (Dextran Sulfate Sodium)-induced colitis mouse model and tissue clearing technology to validate the “targeted nuclear degranulation” of neutrophils in an inflammatory intestinal environment and their migration to the lungs.

Results:

  • Neutrophils from UC patients exhibited higher levels of nuclear degranulation in peripheral blood.
  • Using the DSS mouse model, researchers observed neutrophils migrating from the intestinal mucosa to the lungs, where they were activated during pulmonary infections, rapidly releasing large amounts of NETs, thereby exacerbating lung inflammation.

2. Mechanism of Targeted Nuclear Degranulation

The study further investigated the mechanisms of targeted nuclear degranulation in neutrophils, revealing that changes in the neutrophil cytoskeleton and its interaction with the nuclear membrane are primary mechanisms. Electron microscopy confirmed the fusion of granules with the nuclear membrane. Additionally, the study found that inhibiting cytoskeletal changes and CD44 protein nuclear transport effectively reduced NETs formation.

Results:

  • The cytoskeleton inhibitor Cytochalasin B and the CD44 transport protein inhibitor Importin effectively suppressed the translocation of MPO (Myeloperoxidase) into the nucleus, thereby reducing NETs formation.
  • CD44 mediates the proximity of granules to the nuclear membrane through its interaction with F-actin and the nuclear membrane, ultimately leading to nuclear degranulation.

3. Establishment and Validation of Pulmonary Infection Model

The study validated the role of targeted nuclear degranulation in promoting lung inflammation using the DSS mouse model and lipopolysaccharide (LPS)-induced pulmonary infection. Researchers injected fluorescently labeled neutrophils into the intestinal wall of mice and observed their migration to the lungs using tissue clearing technology, where they released large amounts of NETs during pulmonary infection.

Results:

  • DSS mice exhibited more severe inflammatory responses after pulmonary infection, with significantly increased lung wet-to-dry ratios and elevated levels of inflammatory factors (e.g., IL-6 and IL-17A).
  • Neutrophils originating from the intestines significantly increased the severity of lung inflammation by releasing NETs in the lungs.

Conclusion and Significance

This study revealed that neutrophils in UC patients migrate from the intestinal mucosa to the lungs through the targeted nuclear degranulation mechanism, releasing large amounts of NETs during pulmonary infections, thereby exacerbating lung inflammation. This discovery provides new insights and potential therapeutic targets for treating pulmonary infections in UC patients.

Research Highlights:

  • First to elucidate the specific mechanism of targeted nuclear degranulation in neutrophils during pulmonary infections in UC patients.
  • Visualized the migration of neutrophils from the intestines to the lungs using the DSS mouse model and tissue clearing technology.
  • Identified the critical role of the CD44/F-actin/nuclear membrane complex in nuclear degranulation, offering new targets for future drug development.

Application Value:

  • Provides a new theoretical basis for treating pulmonary infections in UC patients.
  • Inhibiting targeted nuclear degranulation in neutrophils may effectively alleviate lung inflammation and improve patient prognosis.

Other Valuable Information

The study also found that glucocorticoids (Dexamethasone) effectively inhibit the fusion of granules with the nuclear membrane, thereby reducing NETs formation. This discovery provides new scientific evidence for the use of glucocorticoids in inflammatory diseases.

Summary

Through multi-layered experimental design and advanced techniques, this study thoroughly investigated the specific mechanisms of neutrophils in pulmonary infections in UC patients, revealing the critical role of targeted nuclear degranulation in the progression of inflammation. This research not only provides new insights into the treatment of UC but also offers significant theoretical support for strategies to manage pulmonary infections.