Purinergic receptor agonists modulate phagocytosis and clearance of apoptotic cells in macrophages.
Phagocytosis plays an important role in controlling inflammation and antigen cross-presentation through the uptake of apoptotic bodies from dying cells. As dying cells are known to release nucleotides and other "danger signals", we investigated whether extracellular nucleotides may affect phagocytosis through binding to P2 purinergic receptors on phagocytic cells. We here show that the purinergic receptor agonists, ATP, ADP, α,β-methylene ATP (α,β-meATP), 3'-O-(4-benzoyl)benzoyl ATP, UTP and UDP, increased phagocytosis of latex beads, and some of them increased endocytosis and/or macropinocytosis of dextran by macrophages. The enhanced phagocytosis could be inhibited by pre-treatment with the P2X and P2Y antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid and suramin, and the P2Y₁-selective antagonist, MRS2179. The nucleotides induced upregulation in macrophages of the β2 integrin CD11b/CD18 (Mac-1) and the vitronectin receptor (α(v)β3, CD51/CD61), both of which are involved in recognition and internalization of apoptotic cells. In addition, ATP and α,β-meATP increased adhesion of apoptotic cells to macrophages, both in vitro and in vivo, and α,β-meATP had a small effect on adhesion of necrotic cells. The nucleotides had no effect on adhesion of viable cells. We propose that engagement of the P2 receptors (P2X₁, or P2X₃) by extracellular nucleotides released from dying cells increases the ability of macrophages to bind apoptotic bodies, thus enhancing their ability to internalize and present antigens from the dying cells.
Marques-da-Silva
Camila
C
Immunobiology Program, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941, Brazil.
Burnstock
Geoffrey
G
Ojcius
David M
DM
Coutinho-Silva
Robson
R
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D057899:Cytophagocytosis / Q000187:drug effects / Q000276:immunology; D003911:Dextrans / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009711:Nucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D058911:Purinergic P2X Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058912:Purinergic P2Y Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D058469:Receptors, Purinergic P2X / Q000276:immunology / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000276:immunology / Q000378:metabolism*; D013451:Sulfonic Acids / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology
D003911:Dextrans; D039302:Integrin alphaVbeta3; D016177:Macrophage-1 Antigen; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D009711:Nucleotides; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; D013451:Sulfonic Acids; C405633:pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate); D011732:Pyridoxal Phosphate; D013498:Suramin; D000244:Adenosine Diphosphate