The function of TRP channels in neutrophil granulocytes

Abstract

Neutrophil granulocytes are exposed to widely varying microenvironmental conditions when pursuing their physiological or pathophysiological functions such as fighting invading bacteria or infiltrating cancer tissue. Examples for harsh environmental challenges include among others mechanical shear stress during the recruitment from the vasculature or the hypoxic and acidotic conditions within the tumor microenvironment. Chemokine gradients, reactive oxygen species, pressure, matrix elasticity, and temperature can be added to the list of potential challenges. Transient receptor potential (TRP) channels serve as cellular sensors since they respond to many of the abovementioned environmental stimuli. The present review investigates the role of TRP channels in neutrophil granulocytes and their role in regulating and adapting neutrophil function to microenvironmental cues. Following a brief description of neutrophil functions, we provide an overview of the electrophysiological characterization of neutrophilic ion channels. We then summarize the function of individual TRP channels in neutrophil granulocytes with a focus on TRPC6 and TRPM2 channels. We close the review by discussing the impact of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on neutrophil granulocytes. Since neutrophil infiltration into PDAC tissue contributes to disease progression, we propose neutrophilic TRP channel blockade as a potential therapeutic option.

Intricate Interplay between Innate Immune Cells and TRMP2 in a Mouse Model of Multiple Sclerosis

“…Although this proposed mechanism is consistent with the results, it does not consider several other possible interpretations. TRPM2 is indeed expressed by multiple types of innate immune cell (Syed Mortadza et al, 2015), including monocytes (Yamamoto et al, 2008), neutrophils (Heiner et al, 2003;Najder et al, 2018), and microglia (Miyake et al, 2014). Because TRPM2 deletion in the mice by Tsutsui et al (2018) was not specific to macrophages, the contribution of TRPM2 deletion in these other immune cells must be considered, as discussed below.…”

Synergic and comparative effect of 5-fluorouracil and leucoverin on breast and colon cancer cells through TRPM2 channels

“…The selectivity of TRP channels has a wide spectrum, ranging from nonselective cation channels to highly selective (Ca 2+ ) channels. TRP channels respond to a variety of stimuli such as: ligands, heat, mechanical stimulation, and play a role in different processes such as intracellular (Ca 2+ ) metabolism, phagocytosis, cell motility, haemostasis, and infl ammation (32)(33)(34). A number of studies revealed the effects of subpopulations of TRP channels on many different cancer cells and the relationship between the survival and the expression of TRP channels in these cancers have been clearly demonstrated (35).…”

Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels

“…DAG can directly activate members of the transient receptor potential (TRP) channel family, like TRPC6, leading to Ca 2+ influx from the extracellular space [9]. Several Ca 2+ -permeable channels such as Orai1 channels [8,10] as well as TRPC1 [11], TRPC6 [12,13], TRPM2 [14], and TRPV4 channels [15] in neutrophils have been shown to be involved in their recruitment (reviewed in [16,17]). However, the elucidation of the underlying mechanisms by which these Ca 2+ influx channels regulate neutrophil recruitment is complicated by the multitude of chemoattractants.…”

“…However, the elucidation of the underlying mechanisms by which these Ca 2+ influx channels regulate neutrophil recruitment is complicated by the multitude of chemoattractants. While there seems to be a coupling between TRPC6 channels and CXCR2, data concerning the link between TRPM2 channels and fMLPtriggered signaling are discussed controversially [16]. It is further complicated by the fact that Ca 2+ signaling in endothelial (or epithelial) cells has to be considered, too.…”

“…It is further complicated by the fact that Ca 2+ signaling in endothelial (or epithelial) cells has to be considered, too. Indeed, the abovementioned channels are also expressed in endothelial cells [18] and several members of the TRP channel family in endothelial (or epithelial) cells have also been shown to regulate neutrophil recruitment [19][20][21] (reviewed in [16,22]).…”