PROJECT SUMMARY
The contribution of the autonomic nervous system to the development of inflammation is an important
new subject that has massive potential for clinical applications. It has been demonstrated that a7 nicotinic
acetylcholine receptor (a7nAChR) is a critical component of anti-inflammatory cholinergic pathway that
protects an organism during infection, arthritis, diabetes and atherosclerosis. So far, the protective role of
a7nAChR was established only on the prevention of expression of pro-inflammatory cytokines, such as TNFa
and IL-6. However, the mechanism of a7nAChR contribution to inflammatory response seems to be more
comprehensive. One of the most critical steps of the inflammatory response is macrophage migration to the
site of inflammation. The goal of this project is to determine the mechanism of macrophage migration regulated
by the autonomic nervous system. We hypothesize that a7nAChR activation affects macrophage migration
during inflammation by changing the expression of cell adhesive receptors, that modifies the overall a7nAChR-
mediated anti-inflammatory response. Guided by strong preliminary data, this hypothesis will be tested by
pursuing three Specific Aims: 1. Determine the contribution of a7nAChR to macrophage accumulation within
the site of inflammation utilizing in vivo inflammatory models. 2. Evaluate the effect of a7nAChR on
macrophage adhesion and migration using in vitro assays. 3. Define the critical molecules that regulate
a7nAChR-mediated leukocyte migration. Under the first aim, the effect of a7nAChR-deficientcy on
macrophage accumulation during endotoxemia and atherosclerosis will be evaluated. Under the second aim, the
contribution of a7nAChR to macrophage motility will be assessed using in vitro adhesion and migration assays.
Under the third aim, a7nAChR-dependent expression of adhesion and chemokine receptors on macrophages
will be evaluated and analyzed. The significance of our study resides in providing a new insight into the
function of neuro-immune synapse during inflammation. The direct contribution of a7nAChR cholinergic
receptor to monocyte/macrophage migration proposes a new mechanism for the regulation of inflammatory
response though the vagus nerve. This proposal is innovative because most studies of cholinergic anti-
inflammatory mechanisms have focused on the ability of nicotinic agonists to suppress the synthesis and release
of inflammatory cytokines from activated macrophages. We propose the role of neuro-immune synapse in
macrophage migration. The results of our studies will provide completely new information regarding the role of
a7nAChR in inflammation. These findings will be of significant therapeutic interest for targeting a7nAChR to
regulate macrophage migration and to control inflammation in several disorders. The development of anti-
inflammatory treatments is an objective of our further investigations.