RIC3, the cholinergic anti-inflammatory pathway, and neuroinflammation.

ABSTRACT

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels having many functions including inflammation control, as part of the cholinergic anti-inflammatory pathway. Genome wide association studies implicated RIC3, a chaperone of nAChRs, in multiple sclerosis (MS), a neuroinflammatory disease. To understand the involvement of RIC3 in inflammatory diseases we examined its expression, regulation, and function in activated immune cells. Our results show that immune activation leads to dynamic changes in RIC3 expression, in a mouse model of MS and in human lymphocytes and macrophages. We also show similarities in the expression dynamics of RIC3 and CHRNA7, encoding for the α7 nAChR subunit. Homomeric α7 nAChRs were shown to mediate the anti-inflammatory effects of cholinergic agonists. Thus, similarity in expression dynamics between RIC3 and CHRNA7 is suggestive of functional concordance. Indeed, siRNA mediated silencing of RIC3 in a mouse macrophage cell line eliminates the anti-inflammatory effects of cholinergic agonists. Furthermore, we show increased average expression of RIC3 and CHRNA7 in lymphocytes from MS patients, and a strong correlation between expression levels of these two genes in MS patients but not in healthy donors. Together, our results are consistent with a role for RIC3 and for the mechanisms regulating its expression in inflammatory processes and in neuroinflammatory diseases.