Objective: The parasympathetic nervous system regulates inflammation in peripheral tissues through a pathway termed the "cholinergic anti-inflammatory reflex" (CAIR). Mice deficient in the alpha 7 nicotinic acetylcholine receptor (alpha 7(-/-)) have an impaired CAIR due to decreased signaling through this pathway. The purpose of this study was to determine if the increased inflammation in alpha 7(-/-) mice is associated with enhanced serum and macrophage atherogenicity. Methods: We measured serum markers of inflammation and oxidative stress, and macrophage atherogenicity in mouse peritoneal macrophages harvested from alpha 7(-/-) mice on the background of C57BL/6 mice, as well as on the background of the atherosclerotic Apolipoprotein E-deficient (ApoE(-/-)) mice. Results: alpha 7-Deficiency had no significant effects on serum cholesterol, or on markers of serum oxidative stress (TBARS and paraoxonase1 activities). However, alpha 7-deficiency significantly increased serum CRP and IL-6 (p < 0.05) levels in atherosclerotic mice, confirming an anti-inflammatory role for the 0 receptor. Macrophage cholesterol mass was increased by 25% in both normal and atherosclerotic mice in the absence of the alpha 7 receptor (p < 0.05). This was accompanied by conditional increases in oxidized LDL uptake and in macrophage total peroxide levels. Furthermore, alpha 7-deficiency reduced macrophage paraoxonase2 mRNA and activity by 50-100% in normal and atherosclerotic mice (p < 0.05 for each), indicating a reduction in macrophage anti-oxidant capacity in the alpha 7(-/-) mice. Conclusion: The above results suggest an anti-atherogenic role for the macrophage alpha 7nAchr, through a mechanism that involves attenuated macrophage oxidative stress and decreased uptake of oxidized LDL. (c) 2009 Elsevier Inc. All rights reserved.