title: Autocrine purinergic receptor signaling is essential for macrophage chemotaxis.
abstract: Chemotaxis, the movement of cells along chemical gradients, is critical for the recruitment of immune cells to sites of inflammation; however, how cells navigate in chemotactic gradients is poorly understood. Here, we show that macrophages navigate in a gradient of the chemoattractant C5a through the release of adenosine triphosphate (ATP) and autocrine "purinergic feedback loops" that involve receptors for ATP (P2Y(2)), adenosine diphosphate (ADP) (P2Y(12)), and adenosine (A2a, A2b, and A3). Whereas macrophages from mice deficient in pannexin-1 (which is part of a putative ATP release pathway), P2Y(2), or P2Y(12) exhibited efficient chemotactic navigation, chemotaxis was blocked by apyrase, which degrades ATP and ADP, and by the inhibition of multiple purinergic receptors. Furthermore, apyrase impaired the recruitment of monocytes in a mouse model of C5a-induced peritonitis. In addition, we found that stimulation of P2Y(2), P2Y(12), or adenosine receptors induced the formation of lamellipodial membrane protrusions, causing cell spreading. We propose a model in which autocrine purinergic receptor signaling amplifies and translates chemotactic cues into directional motility.
authors.affiliation: Institut für Physiologie II, Wilhems-Universität Münster, 48149 Münster, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Kronlage
authors.forename: Jian
authors.initials: J
authors.lastname: Song
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.forename: Katrin
authors.initials: K
authors.lastname: Isfort
authors.forename: Tanja
authors.initials: T
authors.lastname: Schwerdtle
authors.forename: Jens
authors.initials: J
authors.lastname: Leipziger
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Conley
authors.forename: Hee-Cheol
authors.initials: HC
authors.lastname: Kim
authors.forename: Sarah
authors.initials: S
authors.lastname: Sargin
authors.forename: Peter
authors.initials: P
authors.lastname: Schön
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schwab
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hanley
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D015936:Complement C5a / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058925:Receptors, Purinergic P2Y12; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C548577:P2ry12 protein, mouse; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D058473:Receptors, Purinergic P2Y2; D000244:Adenosine Diphosphate; D015936:Complement C5a; D000255:Adenosine Triphosphate; D001081:Apyrase