title: 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 Ca(2+) influx but not Ca(2+) 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.
authors: Institute of Physiology II, Westfälische Wilhelms-University, 48149 Münster, Germany. o.lindemann@yahoo.de
authors: Otto
authors: O
authors: Lindemann
authors: Daniel
authors: D
authors: Umlauf
authors: Svetlana
authors: S
authors: Frank
authors: Sandra
authors: S
authors: Schimmelpfennig
authors: Jessica
authors: J
authors: Bertrand
authors: Thomas
authors: T
authors: Pap
authors: Peter J
authors: PJ
authors: Hanley
authors: Anke
authors: A
authors: Fabian
authors: Alexander
authors: A
authors: Dietrich
authors: Albrecht
authors: A
authors: Schwab
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D002118:Calcium; D019869:Phosphatidylinositol 3-Kinases; D023063:Receptors, Interleukin-8B; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D048051:p38 Mitogen-Activated Protein Kinases; C492146:Trpc6 protein, mouse