Autocrine purinergic receptor signaling is essential for macrophage chemotaxis.
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.
Kronlage
Moritz
M
Institut für Physiologie II, Wilhems-Universität Münster, 48149 Münster, Germany.
Song
Jian
J
Sorokin
Lydia
L
Isfort
Katrin
K
Schwerdtle
Tanja
T
Leipziger
Jens
J
Robaye
Bernard
B
Conley
Pamela B
PB
Kim
Hee-Cheol
HC
Sargin
Sarah
S
Schön
Peter
P
Schwab
Albrecht
A
Hanley
Peter J
PJ
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*
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