TRPM2 ion channels steer neutrophils towards a source of hydrogen peroxide

Abstract

Neutrophils must navigate accurately towards pathogens in order to destroy invaders and thus defend our bodies against infection. Here we show that hydrogen peroxide, a potent neutrophil chemoattractant, guides chemotaxis by activating calcium-permeable TRPM2 ion channels and thus generating an intracellular leading-edge calcium “pulse”. The thermal sensitivity of TRPM2 activation means that chemotaxis towards hydrogen peroxide is strongly promoted by small temperature elevations, suggesting that an important function of fever may be to enhance neutrophil chemotaxis by facilitating calcium influx through TRPM2. Chemotaxis towards conventional chemoattractants such as LPS, CXCL2 and C5a does not depend on TRPM2 but is driven in a similar way by leading-edge calcium pulses. Other proposed initiators of neutrophil movement, such as PI3K, Rac and lyn, influence chemotaxis by modulating the amplitude of calcium pulses. We propose that intracellular leading-edge calcium pulses are universal drivers of the motile machinery involved in neutrophil chemotaxis.

Ganoderic acid D prevents oxidative stress‐induced senescence by targeting 14‐3‐3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells

“…Hence, both CaM and CaMKII play major roles in Ca 2+ signal transduction. Consistent with the previous results (Morad et al, 2021; Wang & Joseph, 2000), H 2 O 2 resulted in a significant increase in the expression of CaM and p‐CaMKII in hAMSCs. Moreover, our data indicated that GA‐D inhibited the production of intracellular ROS (Figure 2d,e), while the expression of CaM and p‐CaMKII was significantly inhibited in H 2 O 2 ‐induced senescent hAMSCs after GA‐D treatment (Figure 3c,d).…”

“…Ca 2+ homeostasis is disrupted in senescent cells, and the 14‐3‐3ε isoform regulates intracellular Ca 2+ homeostasis by regulating CaM signaling (Russo et al, 2012). In this study, H 2 O 2 was used to stimulate the senescence of hAMSCs through ROS‐caused DNA damage (Jurk et al, 2012; Menon et al, 2013), whereas exogenous H 2 O 2 could also facilitate extracellular calcium influx, causing calcium dysregulation (Morad et al, 2021; Wang & Joseph, 2000). Disruption of intracellular Ca 2+ homeostasis leads to cell senescence (Kim et al, 2020).…”

DUOX2 regulates secreted factors in virus‐infected respiratory epithelial cells that contribute to neutrophil attraction and activation

“…This points towards a complex regulation of neutrophil migration by a combination of DUOX2‐dependent and DUOX2‐independent factors secreted by ECs. Although chemokines are clearly important for the recruitment of neutrophils, H 2 O 2 is also a potent neutrophil chemoattractant 53,54 . Notably, DUOX‐derived H 2 O 2 was shown to form a concentration gradient, guiding neutrophil toward the wound in zebrafish and drosophila models 55–58 .…”