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The TRPM2 Ion Channel Regulates Inflammatory Functions of Neutrophils During Listeria monocytogenes Infection
Frank H Robledo-Avila1, Juan de Dios Ruiz-Rosado1, Kenneth L Brockman1,2
1Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Abstract:
During infection, phagocytic cells pursue homeostasis in the host via multiple mechanisms that control microbial invasion. Neutrophils respond to infection by exerting a variety of cellular processes, including chemotaxis, activation, phagocytosis, degranulation and the generation of reactive oxygen species (ROS). Calcium (Ca2+) signaling and the activation of specific Ca2+ channels are required for most antimicrobial effector functions of neutrophils. The transient receptor potential melastatin-2 (TRPM2) cation channel has been proposed to play important roles in modulating Ca2+ mobilization and oxidative stress in neutrophils. In the present study, we use a mouse model of Listeria monocytogenes infection to define the role of TRPM2 in the regulation of neutrophils' functions during infection. We show that the susceptibility of Trpm2-/- mice to L. monocytogenes infection is characterized by increased migration rates of neutrophils and monocytes to the liver and spleen in the first 24 h. During the acute phase of L. monocytogenes infection, Trpm2-/- mice developed septic shock, characterized by increased serum levels of TNF-α, IL-6, and IL-10. Furthermore, in vivo depletion of neutrophils demonstrated a critical role of these immune cells in regulating acute inflammation in Trpm2-/- infected mice. Gene expression and inflammatory cytokine analyses of infected tissues further confirmed the hyperinflammatory profile of Trpm2-/- neutrophils. Finally, the increased inflammatory properties of Trpm2-/- neutrophils correlated with the dysregulated cytoplasmic concentration of Ca2+ and potentiated membrane depolarization, in response to L. monocytogenes. In conclusion, our findings suggest that the TRPM2 channel plays critical functional roles in regulating the inflammatory properties of neutrophils and preventing tissue damage during Listeria infection.
Insights
The transient receptor potential melastatin-2 (TRPM2) channel is crucial for regulating neutrophil function during Listeria infection. TRPM2 deficiency leads to hyperinflammation and increased susceptibility to septic shock, highlighting its protective role.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Phagocytic cells, particularly neutrophils, are vital for controlling microbial invasion through various functions like chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation.
- Calcium (Ca2+) signaling and specific Ca2+ channels are essential for neutrophil antimicrobial effector functions.
- The transient receptor potential melastatin-2 (TRPM2) cation channel is implicated in modulating Ca2+ mobilization and oxidative stress in neutrophils.
Purpose of the Study:
- To investigate the role of the TRPM2 channel in regulating neutrophil functions during Listeria monocytogenes infection using a mouse model.
- To determine the impact of TRPM2 deficiency on host susceptibility and inflammatory responses to L. monocytogenes.
Main Methods:
- Utilized a mouse model of Listeria monocytogenes infection.
- Analyzed neutrophil and monocyte migration to liver and spleen.
- Assessed serum cytokine levels (TNF-α, IL-6, IL-10) during acute infection.
- Performed in vivo neutrophil depletion experiments.
- Conducted gene expression and inflammatory cytokine analyses of infected tissues.
- Measured cytoplasmic Ca2+ concentration and membrane potential in neutrophils.
Main Results:
- Trpm2-/- mice exhibited increased neutrophil and monocyte migration to the liver and spleen within 24 hours post-infection.
- Trpm2-/- mice developed septic shock, with elevated serum levels of TNF-α, IL-6, and IL-10.
- Neutrophil depletion studies confirmed the critical role of neutrophils in regulating acute inflammation in Trpm2-/- mice.
- Trpm2-/- neutrophils displayed a hyperinflammatory profile, characterized by dysregulated Ca2+ signaling and membrane depolarization in response to L. monocytogenes.
Conclusions:
- The TRPM2 channel plays a critical role in regulating neutrophil inflammatory properties during Listeria infection.
- TRPM2 deficiency leads to hyperinflammation and increased susceptibility to septic shock.
- TRPM2 channel function is essential for preventing tissue damage and maintaining homeostasis during Listeria infection.
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