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.

Neuroprotective roles of the P2Y2 receptor

“…P2Y 12 and P2X 4 receptor activation has been shown to induce migration of ramified microglia, attracting them to regions of high ATP concentrations [148,149]. Studies using peritoneal macrophages in mice have shown that stimulation of P2Y 2 and P2Y 12 receptors induces the formation of lamellipodial membrane protrusions that leads to cell spreading and efficient directional motility of cells [150]. Taken together, these findings support the hypothesis that extracellular nucleotides serve as endogenous danger signals that activate microglia during the innate immune response.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…76,77 Many of the inflammatory properties of ATP are linked to their stimulation of the P2X 7 R; however, activation of P2X 7 R requires 4100 μM ATP, 74 indicating that 100-200 nM released during cell death is unlikely to activate the P2X 7 R. In fact, this has been supported by studies that showed pannexin-mediated ATP release does not activate P2X 7 R. 78 P2X receptors only engage ATP, while the P2Y receptors, which are implicated in migration, recognize ATP, UTP, and their metabolites. 79 This recognition repertoire can have an important function in cell clearance, as apoptotic cells also release UTP. Furthermore, ATP and UTP can also elicit monocyte migration indirectly by affecting adhesion molecule expression on vascular endothelial cells.…”

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…The co-expression of these enzymes on immune cells has been demonstrated for activated mouse Treg and Th17 cells, 9,10 but untreated human Tregs in the circulation only express low levels of intracellular CD73. 11 Mouse peritoneal macrophages may also co-express these enzymes, 12 whereas healthy non-activated human blood monocytes and macrophages have abundant expression of CD39 but not CD73 on the cell surface. 13,14 Ectonucleotidase expression can be controlled by the microenvironment; e.g., CD39 expression is regulated by IL-27 in ovarian cancer, 15 while CD73 is upregulated by hypoxia on epithelial cells 16 by TGFb on murine leukocytes 17 and by signal-transducer and activator of transcription-3 (STAT3) activation on murine Th17 cells.…”