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A Protocol to Infect Caenorhabditis elegans with Salmonella typhimurium
Published on: June 26, 2014
Loss of NR2F6 Protects from Salmonella Typhimurium Infection
Johannes Woelk1, Christa Pfeifhofer-Obermair2, Julia Benz1,3
1Institute of Cell Genetics, Department for Genetics, Medical University of Innsbruck, Innsbruck, 6020, Austria.
Abstract:
Nuclear receptors regulate key functions of mononuclear phagocytes and are critical components of the innate immune system, acting as regulators of organ health and disease. In healthy mice, the loss of the nuclear orphan receptor NR2F6 alters tissue-resident macrophage populations in the liver, lung, and spleen. In response to Salmonella Typhimurium infection, Nr2f6-deficient mice exhibit improved clinical outcomes, characterized by reduced weight loss, bacterial loads in the spleen and liver, and decreased plasma pro-inflammatory cytokines. Despite unchanged basal iron metabolism in the spleen and liver, iron regulatory proteins and the interleukin (IL)-6-hepcidin axis are altered in Nr2f6-deficient mice during Salmonella infection, reducing hypoferremia. Transcriptomic analysis of splenic red pulp macrophages reveals significant alterations of phagocytosis-related genes, including upregulation of signal-regulatory protein alpha (Sirpa). In vitro, phagocytosis of red blood cells, regulated by the inhibitory CD47-Sirpα axis, and Salmonella Typhimurium phagocytosis are significantly impaired in Nr2f6-deficient splenic macrophages. Blocking Sirpα in vitro restores the phagocytic activity of Nr2f6-deficient macrophages to wild-type levels. In vivo, Salmonella Typhimurium loads are partially increased post-infection in anti-Sirpα treated Nr2f6-deficient mice. These findings uncover a previously unrecognized role of NR2F6 in host-pathogen interactions, positioning it as a potential therapeutic target for infectious diseases.
Insights
The nuclear orphan receptor NR2F6 impacts macrophage function and host defense. Its absence improves outcomes in Salmonella infection by altering the CD47-Sirpα axis, revealing NR2F6 as a potential therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Infectious Diseases
Background:
- Nuclear receptors are crucial for innate immunity and organ health.
- The nuclear orphan receptor NR2F6 influences tissue-resident macrophage populations.
- NR2F6 plays a role in host-pathogen interactions and immune responses.
Purpose of the Study:
- To investigate the role of the nuclear orphan receptor NR2F6 in host defense against Salmonella Typhimurium infection.
- To elucidate the mechanisms by which NR2F6 deficiency affects macrophage function and clinical outcomes.
- To identify NR2F6 as a potential therapeutic target for infectious diseases.
Main Methods:
- Comparative analysis of Nr2f6-deficient and wild-type mice during Salmonella Typhimurium infection.
- Assessment of clinical outcomes, bacterial loads, and plasma cytokine levels.
- Transcriptomic analysis of splenic red pulp macrophages and in vitro phagocytosis assays.
- Investigation of the CD47-Sirpα axis and its role in NR2F6-mediated phagocytosis.
Main Results:
- Nr2f6-deficient mice showed improved outcomes, reduced bacterial loads, and lower pro-inflammatory cytokines during Salmonella infection.
- NR2F6 deficiency altered iron metabolism regulators and the IL-6-hepcidin axis, reducing hypoferremia.
- Splenic macrophages from Nr2f6-deficient mice exhibited impaired phagocytosis of red blood cells and Salmonella, linked to Sirpα upregulation.
- Blocking Sirpα restored phagocytic activity in vitro, and partially increased bacterial loads in vivo in anti-Sirpα treated Nr2f6-deficient mice.
Conclusions:
- NR2F6 plays a significant role in regulating macrophage phagocytosis and host defense against Salmonella Typhimurium.
- The CD47-Sirpα axis is a key mediator of NR2F6's function in splenic macrophages during infection.
- NR2F6 represents a novel therapeutic target for managing infectious diseases.
