Purinergic receptor regulation of LPS-induced signaling and pathophysiology

Abstract

Macrophages express several lipopolysaccharide (LPS) binding proteins and are potently activated by LPS to produce inflammatory mediators. Recent studies have shown that receptors for exogenous nucleotides (P2X and P2Y purinergic receptors) can modulate macrophage production of TNF-α , IL-1β and nitric oxide (NO) following LPS exposure. Macrophages and LPS-stimulated monocytes express elevated levels of P2Y₁, P2Y₂ and P2X₇ mRNA, suggesting that both P2Y and P2X receptors can contribute to LPS-induced pathophysiology. In addition, oxidized-ATP treatment (which inhibits P2X₇) of macrophages blocks LPS-induced NO production, NF-κB and ERK-1/2 activation. Also, an LPS-binding domain located in the P2X₇ C-terminus appears important for receptor trafficking/function. Moreover, the purinergic receptor ligand 2-MeS-ATP attenuates LPS-induced cytokine and NO production in vivo and ex vivo. These data suggest that P2X₇ and certain P2Ys are linked to LPS effects, although their relative contribution in vivo is unclear. Accordingly, we tested the capacity of several adenine nucleotides to modulate LPS-induced mortality in mice. We found that the P2X₇-directed ligand BzATP was unable to prevent LPS-induced death, whereas 2-MeS-ATP and 2-Cl-ATP, which bind to multiple P2X and P2Y receptors were able to protect mice from LPS-induced death. These data suggest that the co-ordinate action of P2Y and P2X₇ receptors are critical for controlling LPS responses in vivo and that agents directed against both receptor classes may provide the greatest therapeutic advantage.