α7 Nicotinic Acetylcholine Receptor (α7nAChR) Expression in Bone Marrow-Derived Non-T Cells Is Required for the Inflammatory Reflex

Olofsson, Peder S.; Katz, David A.; Rosas-Ballina, Mauricio; Levine, Yaakov A.; Ochani, Mahendar; Valdés-Ferrer, Sergio; Pavlov, Valentin A.; Tracey, Kevin J.; Chavan, Sangeeta S.

doi:10.2119/molmed.2011.00405

Cited by 137 publications

(112 citation statements)

References 27 publications

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“…Previous studies in several preclinical models of systemic inflammation have convincingly demonstrated that the CAIP requires the presence of α7nAChR;2 31 however, the role of α7nAChR and the cells expressing this receptor in the gut have not been established. Therefore, to evaluate the contribution of this receptor to the vagal anti-inflammatory effect in the intestine, α7nAChR −/− knockout mice24 were subjected to IM with or without VNS, as described above.…”

Section: Resultsmentioning

confidence: 99%

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

Matteoli

Gomez‐Pinilla

Némethova

et al. 2013

Gut

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361

340

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The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagus nerve stimulation (VNS) reduces intestinal inflammation and improves postoperative ileus. We investigated the neural pathway involved and the cells mediating the anti-inflammatory effect of VNS in the gut. The effect of VNS on intestinal inflammation and transit was investigated in wild-type, splenic denervated and Rag-1 knockout mice. To define the possible role of α7 nicotinic acetylcholine receptor (α7nAChR), we used knockout and bone marrow chimaera mice. Anterograde tracing of vagal efferents, cell sorting and Ca(2+) imaging were used to reveal the intestinal cells targeted by the vagus nerve. VNS attenuates surgery-induced intestinal inflammation and improves postoperative intestinal transit in wild-type, splenic denervated and T-cell-deficient mice. In contrast, VNS is ineffective in α7nAChR knockout mice and α7nAChR-deficient bone marrow chimaera mice. Anterograde labelling fails to detect vagal efferents contacting resident macrophages, but shows close contacts between cholinergic myenteric neurons and resident macrophages expressing α7nAChR. Finally, α7nAChR activation modulates ATP-induced Ca(2+) response in small intestine resident macrophages. We show that the anti-inflammatory effect of the VNS in the intestine is independent of the spleen and T cells. Instead, the vagus nerve interacts with cholinergic myenteric neurons in close contact with the muscularis macrophages. Our data suggest that intestinal muscularis resident macrophages expressing α7nAChR are most likely the ultimate target of the gastrointestinal CAIP.

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Section: Resultsmentioning

confidence: 99%

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

Matteoli

Gomez‐Pinilla

Némethova

et al. 2013

Gut

Self Cite

361

340

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“…2. Then via α7 nAChRs on macrophages, ACh down-regulates synthesis of pro-inflammatory cytokines such as TNF-α [19,66,67,80]. SLURP-1 released from CD205 + SLURP-1 + DCs should potentiate the action of ACh at α7 nAChRs on macrophages, enhancing its modulation of pro-inflammatory cytokine production.…”

Section: α7 Nachrs and The Regulation Of Immune Functionmentioning

confidence: 99%

“…SLURP-1 released from CD205 + SLURP-1 + DCs should potentiate the action of ACh at α7 nAChRs on macrophages, enhancing its modulation of pro-inflammatory cytokine production. Oloffson et al [80] suggested α7 nAChRs expressed in non-T cell bone marrow-derived immune cells, together with splenic AChproducing T cells, are necessary for normal function of the inflammatory reflex leading to modulation of TNF-α synthesis. As described above, however, α7 nAChRs on T cells also act within the inflammatory reflex by stimulating ACh synthesis and release, thereby regulating proinflammatory cytokine production by macrophages [65].…”

Section: α7 Nachrs and The Regulation Of Immune Functionmentioning

confidence: 99%

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

Kawashima

Fujii

Moriwaki

et al. 2015

International Immunopharmacology

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In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including α7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M(1)/M(5) mAChR signaling up-regulates IgG(1) and pro-inflammatory cytokine production, while α7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric α7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating α7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation.

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“…Norepinephrine released by celiac ganglion inter-neurons binds through adrenergic receptors on memory T cells with intrinsic ability to synthesize acetylcholine [8]. In contrast to classic parasympathetic signaling through muscarinic receptors, T-cellderived acetylcholine binds to α7nAChR on mononuclear cells and macrophages in the red pulp and marginal zone inhibiting cytokine production [7,9]. Activation of α7nAChR inhibits nuclear factor (NF)-κB translocation resulting in decreased transcription of cytokine genes [4,5].…”

Section: Molièrementioning

confidence: 99%

Neuroimmunomodulation: A new frontier of treating cardiovascular diseases

Stavrakis

2016

Trends in Cardiovascular Medicine

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α7 Nicotinic Acetylcholine Receptor (α7nAChR) Expression in Bone Marrow-Derived Non-T Cells Is Required for the Inflammatory Reflex

Cited by 137 publications

References 27 publications

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

Neuroimmunomodulation: A new frontier of treating cardiovascular diseases

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