Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response.
When challenged with extracellular ATP, leukocytes respond and activate processes attributed to the P2X(7) receptor (P2X(7)R), an unusual ligand-gated ion channel. To prove P2X(7)R involvement, blood samples from P2X(7)R-deficient mice were characterized. Monocytes and lymphocytes associated with wild-type blood responded to ATP and underwent volume/shape changes and shed L-selectin. In contrast, leukocytes from P2X(7)R-deficient animals demonstrated no change in physical properties or L-selectin expression following ATP challenge. Blood stimulated with LPS or ATP individually generated minimal quantities of the leaderless polypeptide IL-1 beta, but sequential treatment of wild-type, but not P2X(7)R-deficient, blood with LPS and ATP yielded large amounts of cell-free cytokine. Based on these differences, wild-type and P2X(7)R-deficient animals were compared following induction of monoclonal anti-collagen-induced arthritis. Ab-treated wild-type animals subsequently challenged with LPS developed inflamed, swollen paws; their joint cartilage demonstrated lesions, loss of proteoglycan content, and the presence of collagen degradation products. P2X(7)R-deficient animals subjected to the same challenge were markedly less affected; both the incidence and severity of disease were reduced. These data indicate that ATP does act via the P2X(7)R to affect leukocyte function and that the P2X(7)R can serve as an important component of an in vivo inflammatory response.
Labasi
Jeffrey M
JM
Department of Antibacterials, Immunology, and Inflammation, Pfizer Global Research and Development, Pfizer Inc., Groton, CT 06340, USA.
Petrushova
Nina
N
Donovan
Carol
C
McCurdy
Sandra
S
Lira
Paul
P
Payette
Mary M
MM
Brissette
William
W
Wicks
Joan R
JR
Audoly
Laurent
L
Gabel
Christopher A
CA
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis / Q000097:blood; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018048:Receptors, Purinergic P2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D058486:Receptors, Purinergic P2X7; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D007375:Interleukin-1; D008070:Lipopolysaccharides; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D019041:L-Selectin; D000255:Adenosine Triphosphate