Vagus nerve activity augments intestinal macrophage phagocytosis via nicotinic acetylcholine receptor alpha4beta2.
OBJECTIVE
The vagus nerve negatively regulates macrophage cytokine production via the release of acetylcholine (ACh) and activation of nicotinic acetylcholine receptors (nAChR). In various models of intestinal inflammation, vagus nerve efferent stimulation ameliorates disease. Given the actively constrained cytokine responses of intestinal macrophages, we explored the effect of nAChR activation on endocytosis and phagocytosis by macrophages residing in the peritoneal and mucosal compartment.


METHODS
The phagocytic uptake by intestinal and peritoneal macrophages was measured by fluorescence-activated cell sorter analysis, and the nAChR involved was determined by pharmacologic blockade, short hairpin RNA-assisted gene knockdown, and the use of specific nAChR knockout mice. The effect of electrical vagus nerve stimulation on epithelial translocation and macrophage uptake of luminal particles was studied in mice.


RESULTS
In isolated intestinal and peritoneal macrophages, nAChR activation enhanced endocytosis and phagocytosis. This effect was mediated via stimulated recruitment of GTPase Dynamin-2 to the forming phagocytic cup. These effects involve nAChR alpha4/beta2, rather than nAChR alpha7. Despite enhanced bacterial uptake, acetylcholine reduced NF-kappaB activation and pro-inflammatory cytokine production, while stimulating anti-inflammatory interleukin-10 production. Vagus nerve stimulation in mice altered mucosal immune responses by augmenting epithelial transport and uptake of luminal bacteria by lamina propria macrophages.


CONCLUSIONS
ACh enhances phagocytic potential while inhibiting immune reactivity via nAChR alpha4/beta2 in mouse macrophages. Hence, vagus nerve efferent activity may stimulate surveillance in the intestinal mucosa and peritoneal compartment.
Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
Esmerij P
EP
van der Zanden
Susanne A
SA
Snoek
Sigrid E
SE
Heinsbroek
Oana I
OI
Stanisor
Caroline
C
Verseijden
Guy E
GE
Boeckxstaens
Maikel P
MP
Peppelenbosch
David R
DR
Greaves
Siamon
S
Gordon
Wouter J
WJ
De Jonge
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D034285:Dynamin II / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000166:cytology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology; D010587:Phagocytosis; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014630:Vagus Nerve / Q000502:physiology*
D018679:Cholinergic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D034285:Dynamin II; D000109:Acetylcholine