Cholinergic Signaling in the Gut: A Novel Mechanism of Barrier Protection through Activation of Enteric Glia Cells

Cheadle, Gerald; Costantini, Todd W.; Bansal, Vishal; Eliceiri, Brian P.; Coimbra, Raúl

doi:10.1089/sur.2013.103

Cited by 41 publications

(42 citation statements)

References 33 publications

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“…As a role for α7nAChRs in leukocyte homeostasis is unequivocal (16), CHRFAM7A might then confer leukocytes with a humanspecific responsiveness to trophic stimuli that remains to be defined. In one example, efferent signaling of the vagus nerve has a central role in regulating inflammation and α7nAChR activation is an obligatory intermediate, at least in mice (2,(16)(17)(18)(19)29,63,64). If the vagus nerve were presumed to have a similarly critical role in maintaining immune homeostasis in humans, then CHRFAM7A would likely gauge the immunomodulatory properties of human α7nAChR in a human-specific manner.…”

Section: Resultsmentioning

confidence: 99%

“…As recently reviewed by Costantini et al (2) and Sinkus et al (3), it was almost twenty years later that Gault et al (4) sequenced the human α7nAChR gene on chromosome 15q13-14 and found it to be structurally similar to that of all other species. At the same time, however, they noted the presence of a second, human-specific partially duplicated α7nAChR-like gene that localized 1.6 Mb 5′ upstream from human CHRNA7 (4).…”

Section: Introductionmentioning

confidence: 98%

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A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Costantini

Dang

Yurchyshyna

et al. 2015

Mol Med

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The human genome contains a variant form of the α7-nicotinic acetylcholine receptor (α7nAChR) gene that is uniquely human. This CHRFAM7A gene arose during human speciation and recent data suggests that its expression alters ligand tropism of the normally homopentameric human α7-AChR ligand-gated cell surface ion channel that is found on the surface of many different cell types. To understand its possible significance in regulating inflammation in humans, we investigated its expression in normal human leukocytes and leukocyte cell lines, compared CHRFAM7A expression to that of the CHRNA7 gene, mapped its promoter and characterized the effects of stable CHRFAM7A overexpression. We report here that CHRFAM7A is highly expressed in human leukocytes but that the levels of both CHRFAM7A and CHRNA7 mRNAs were independent and varied widely. To this end, mapping of the CHRFAM7A promoter in its 5′-untranslated region (UTR) identified a unique 1-kb sequence that independently regulates CHRFAM7A gene expression. Because overexpression of CHRFAM7A in THP1 cells altered the cell phenotype and modified the expression of genes associated with focal adhesion (for example, FAK, P13K, Akt, rho, GEF, Elk1, CycD), leukocyte transepithelial migration (Nox, ITG, MMPs, PKC) and cancer (kit, kitL, ras, cFos cyclinD1, Frizzled and GPCR), we conclude that CHRFAM7A is biologically active. Most surprisingly however, stable CHRFAM7A overexpression in THP1 cells upregulated CHRNA7, which, in turn, led to increased binding of the specific α7nAChR ligand, bungarotoxin, on the THP1 cell surface. Taken together, these data confirm the close association between CHRFAM7A and CHRNA7 expression, establish a biological consequence to CHRFAM7A expression in human leukocytes and support the possibility that this human-specific gene might contribute to, and/or gauge, a human-specific response to inflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Costantini

Dang

Yurchyshyna

et al. 2015

Mol Med

Self Cite

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“…The concentrations of nicotine used in our cell culture studies were derived from detailed dose-response testing, were noncytotoxic, and induced significant effects at levels higher than those absorbed in the circulation by individuals who smoke, but which may be achieved in tissue levels with high nicotine concentrations, such as the lung (6,30). The effect of nicotine on barrier function may be organ dependent because other studies have shown an improvement in the gut barrier function by cholinergic actions of nicotine on enteric glial cells (4).…”

Section: Discussionmentioning

confidence: 99%

Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures

Schweitzer

Chen

Law

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

223

190

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The increased use of inhaled nicotine via e-cigarettes has unknown risks to lung health. Having previously shown that cigarette smoke (CS) extract disrupts the lung microvasculature barrier function by endothelial cell activation and cytoskeletal rearrangement, we investigated the contribution of nicotine in CS or e-cigarettes (e-Cig) to lung endothelial injury. Primary lung microvascular endothelial cells were exposed to nicotine, e-Cig solution, or condensed e-Cig vapor (1-20 mM nicotine) or to nicotine-free CS extract or e-Cig solutions. Compared with nicotine-containing extract, nicotine free-CS extract (10-20%) caused significantly less endothelial permeability as measured with electric cell-substrate impedance sensing. Nicotine exposures triggered dose-dependent loss of endothelial barrier in cultured cell monolayers and rapidly increased lung inflammation and oxidative stress in mice. The endothelial barrier disruptive effects were associated with increased intracellular ceramides, p38 MAPK activation, and myosin light chain (MLC) phosphorylation, and was critically mediated by Rho-activated kinase via inhibition of MLC-phosphatase unit MYPT1. Although nicotine at sufficient concentrations to cause endothelial barrier loss did not trigger cell necrosis, it markedly inhibited cell proliferation. Augmentation of sphingosine-1-phosphate (S1P) signaling via S1P1 improved both endothelial cell proliferation and barrier function during nicotine exposures. Nicotine-independent effects of e-Cig solutions were noted, which may be attributable to acrolein, detected along with propylene glycol, glycerol, and nicotine by NMR, mass spectrometry, and gas chromatography, in both e-Cig solutions and vapor. These results suggest that soluble components of e-Cig, including nicotine, cause dose-dependent loss of lung endothelial barrier function, which is associated with oxidative stress and brisk inflammation.

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“…mechanism for this effect (58)(59)(60). Enteric glia express TLRs, and these are differentially upregulated in response to pathogenic and non-pathogenic bacteria (61,62).…”

Section: Role Of Enteric Glia In Brain Disordersmentioning

confidence: 99%

Emerging roles for enteric glia in gastrointestinal disorders

Sharkey¹

2015

J. Clin. Invest.

161

131

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Cholinergic Signaling in the Gut: A Novel Mechanism of Barrier Protection through Activation of Enteric Glia Cells

Cited by 41 publications

References 33 publications

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

A Human-Specific α7-Nicotinic Acetylcholine Receptor Gene in Human Leukocytes: Identification, Regulation and the Consequences of CHRFAM7A Expression

Endothelial disruptive proinflammatory effects of nicotine and e-cigarette vapor exposures

Emerging roles for enteric glia in gastrointestinal disorders

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