Cholinergic modulation of microglial activation by α7 nicotinic receptors

Abstract

Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via a7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express a7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunochistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-a release in murine-derived microglial cells, an effect attenuated by a7 selective nicotinic antagonist, a-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through a7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

“…This anti-inflammatory potential of acetylcholine and nicotine is based on the inhibition of the NF-κB pathway through a specific nicotinic anti-inflammatory pathway' dependent on the alpha7nAChR (Wang et al, 2004). The inhibition of TNF production in LPS-stimulated microglial cultures is also associated with a reduction in the activation of ERK and p38MAPK (Shytle et al, 2004;Suzuki et al, 2006) (Fig. 2).…”

“…Nicotine induces anti-inflammatory mechanisms that diminish local inflammatory responses (Hellstrom-Lindahl et al, 2004a;Streit, 2002;Wang et al, 2000a, b). Among other, nicotine abrogates the production of TNF in culture of microglia through a mechanism dependent on ERK and p38 MAPK (Shytle et al, 2004;Suzuki et al, 2006). Experimental models of AD indicate that alpha7nAChR is the central core of the nicotine-mediated neuroprotection.…”

“…However, microglia can also be neurotoxic by producing free radicals, inflammatory cytokines and other toxic factors. Recent studies indicate that neurons and astrocytes can regulate innate immune responses in microglia via both alpha7nAChRs and purinergic P2X 7 receptors (Shytle et al, 2004;Suzuki et al, 2006). Primary cultures of both resting and actívate microglia and astrocytes show choline acetyltransferase (ChAT) activity and synthesize acetylcholine (De Rosa et al, 2005) suggesting that this neurotransmitter act as a local immune regulator and contribute to the regulation of microglial functions.…”

“…On the other hand, LPSstimulated microglia causes massive TNF production leading to inflammation (Suzuki et al, 2006). Acetylcholine and nicotine inhibit the production of TNF in LPS-stimulated mouse microglial cultures (De Rosa et al, 2005;Shytle et al, 2004). This anti-inflammatory potential of acetylcholine and nicotine is based on the inhibition of the NF-κB pathway through a specific nicotinic anti-inflammatory pathway' dependent on the alpha7nAChR (Wang et al, 2004).…”

Carbachol inhibits TNF-α-induced endothelial barrier dysfunction through alpha 7 nicotinic receptors

“…Also, others have reported that administration of acetylcholine inhibits LPSinduced TNF-α release by a reduction in phosphorylation of MAPKs. This inhibitory effect of acetylcholine is blocked by α-bungarotoxin, a specific antagonist of alpha 7 nAChR [17] . Our present study indicates that α-bungarotoxin blocks the effect of carbachol on ERK1/2 and JNK activation and the expression of VE-cadherin and ICAM-1 in endothelial cells.…”