The cholinergic anti-inflammatory pathway of the intestine: a neuro-immune feedback loop with great therapeutic potential
01 / 2008 - unknown
It is well established that the vagus nerve plays an important immunosensory role and informs the brain about peripheral inflammation and/or infection. Conversely, we showed in a mouse model of postoperative ileus that stimulation of vagal efferents dampens intestinal inflammation by inhibition of macrophages. This effect is mediated by stimulation of alpha 7 nicotinic acetylcholine receptors ( Ñ7 nAChR) on macrophages leading to reduced release of cytokines. Based on these findings, the intriguing hypothesis was forwarded that the brain integrates vagal immunosensory information and as part of an inflammatory reflex activates the efferent vagus nerve to locally modulate the immune system. However, anatomical and functional data supporting this concept are lacking. Therefore, key objective 1 is to show activation of the anti-inflammatory pathway in response to inflammation and to characterize the key neural pathways and immune cells involved. Key objective 2 stems from preliminary results from our laboratory suggesting that the macrophage ¡§anti-inflammatory¡¨ Ñ7 nAChR differs from the classic neuronal Ñ7 nAChR and may not function as an ion channel. Ultimately, this receptor subtype may have different pharmacological properties, which is of great importance for future drug development. To test this provocative hypothesis, we will characterize and functionally analyze the macrophage Ñ7 nAChR and the downstream signalling pathways activated, and address the questioned function as an ion channel. Key objective 3 is to study the therapeutic potential of selective activation of the cholinergic anti-inflammatory pathway: the anti-inflammatory effect of selective Ñ7 nAChR agonists will be evaluated in vitro and in vivo (postoperative ileus and colitis mouse model). Next, clinical trials will be designed to evaluate the effect of treatment with a specific Ñ7 nAChR agonist in postoperative ileus and ulcerative colitis.