Absence of the P2X7 Receptor Alters Leukocyte Function and Attenuates an Inflammatory Response

Abstract

When challenged with extracellular ATP, leukocytes respond and activate processes attributed to the P2X₇ receptor (P2X₇R), an unusual ligand-gated ion channel. To prove P2X₇R involvement, blood samples from P2X₇R-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 P2X₇R-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-1β, but sequential treatment of wild-type, but not P2X₇R-deficient, blood with LPS and ATP yielded large amounts of cell-free cytokine. Based on these differences, wild-type and P2X₇R-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. P2X₇R-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 P2X₇R to affect leukocyte function and that the P2X₇R can serve as an important component of an in vivo inflammatory response.