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.
Highlights
Polymorphonuclear cells (PMNs), commonly called neutrophils, are the first line of defense of the host against microbial infections [1,2,3]
We found that Trpm2−/− neutrophils produced more oxidative products when cells were stimulated with phorbol 12-myristate 13-acetate (PMA) (Figure 6A) or L. monocytogenes compared to WT neutrophils (Figure 6B)
The plasma membrane was stained using the lectin wheat germ agglutinin (WGA). Both WT and Trpm2−/− neutrophils produced neutrophil extracellular traps (NETs) under the stimulation with H2O2, PMA or L. monocytogenes. (B) WT, Trpm2−/− or Nox2−/− neutrophils were stimulated with PMA, SyTOX green was added and kinetic of extracellular DNA (NETosis) was measured by fluorescence plate reader, the graph represents the mean ± SD
Summary
Polymorphonuclear cells (PMNs), commonly called neutrophils, are the first line of defense of the host against microbial infections [1,2,3]. TRPM2 Regulates Neutrophils’ Inflammatory Responses or the production of neutrophil extracellular traps (NETs) [1, 6], these mechanisms are in part regulated by mobilization of calcium (Ca2+) and the subsequent Ca2+ signaling events [7, 8]. Ca2+ release-activated channels (CRAC) are considered the main ion channels responsible for the regulation of Ca2+ entry in immune cells [7, 9], the transient receptor potential (TRP) superfamily have emerged as crucial ion channels that regulate specific cell processes in myeloid cells 2 (TRPM2), has been proposed to regulate inflammatory responses in myeloid cells [13,14,15,16]. TRPM2 is a Ca2+ permeable, non-selective cation channel, which is activated by ADPribose (ADPR), temperature, oxidative stress and Ca2+ [17]
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