TRPC6 Regulates CXCR2-Mediated Chemotaxis of Murine Neutrophils

Abstract

Unraveling the mechanisms involved in chemotactic navigation of immune cells is of particular interest for the development of new immunoregulatory therapies. It is generally agreed upon that members of the classical transient receptor potential channel family (TRPC) are involved in chemotaxis. However, the regulatory role of TRPC channels in chemoattractant receptor-mediated signaling has not yet been clarified in detail. In this study, we demonstrate that the TRPC6 channels play a pronounced role in CXCR2-mediated intermediary chemotaxis, whereas N-formyl-methionine-leucine-phenylalanine receptor–mediated end-target chemotaxis is TRPC6 independent. The knockout of TRPC6 channels in murine neutrophils led to a strongly impaired intermediary chemotaxis after CXCR2 activation which is not further reinforced by CXCR2, PI3K, or p38 MAPK inhibition. Furthermore, CXCR2-mediated Ca2+ influx but not Ca2+ store release was attenuated in TRPC6−/− neutrophils. We demonstrate that the TRPC6 deficiency affected phosphorylation of AKT and MAPK downstream of CXCR2 receptor activation and led to altered remodeling of actin. The relevance of this TRPC6-depending defect in neutrophil chemotaxis is underscored by our in vivo findings. A nonseptic peritoneal inflammation revealed an attenuated recruitment of neutrophils in the peritoneal cavity of TRPC6−/− mice. In summary, this paper defines a specific role of TRPC6 channels in CXCR2-induced intermediary chemotaxis. In particular, TRPC6-mediated supply of calcium appears to be critical for activation of downstream signaling components.

Ion channels and transporters in tumour cell migration and invasion

“…Calcium-dependent development of mechanical force also has a large impact on cell adhesion which is detailed below. In neutrophil granulocytes, the ablation of TRPC6 channels caused a severe impairment of the cells to chemotax towards the KC (CXCL1) [60]. Local TRPM7-mediated Ca 2þ sparks at the cell front are required for directional migration of fibroblasts towards a source of platelet-derived growth factor (PDGF) [53].…”

Gene expressions of TRP channels in glioblastoma multiforme and relation with survival

“…Examples include TRPV2-dependent migration of macrophages [24], chemotaxis of monocytes relying on TRPC3 channels [25], TRPM7-dependent polarization and fibroblast migration [26], and TRPC6-dependent chemotaxis of neutrophils [27,28]. About 30 TRPs have been identified, and they are classified into six different families: TRPA (ankyrin transmembrane protein), TRPV (vanilloid), TRPC (canonical), TRPM (melastatin), TRPP (polycystin), and TRPML (mucolipin) [29].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…It is noteworthy that TRPC6 is expressed in podocytes, where it is required for establishing the glomerular filtration barrier (Reiser et al, 2005). TRPC6 also plays an activating role in cell migration downstream of the CXC-type, G q proteincoupled chemokine receptors and TRPC6 downregulation strongly impairs the chemotaxis of neutrophils Lindemann et al, 2013).…”