Olofsson_2012_Mol.Med_18_539

The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of alpha7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and alpha7nAChR-deficient mice. Deficiency of alpha7nAChR in bone marrow-derived cells significantly impaired vagus nerve-mediated regulation of tumor necrosis factor (TNF), whereas alpha7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell alpha7nAChR, we adoptively transferred alpha7nAChR-deficient or WT T cells to nude mice. Transfer of WT and alpha7nAChR-deficient T cells restored function, indicating that alpha7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that alpha7nAChR expression in bone marrow-derived non-T cells is required for the integrity of the inflammatory reflex.