Acetylcholine polarizes dendritic cells toward a Th2-promoting profile

Gori, Soledad; Vermeulen, Mónica; Remes-Lenicov, Federico; Jancic, Carolina; Scordo, Walter; Ceballos, Ana; Towstyka, Nadia Yasmín; Bestach, Yesica Soledad; Belli, Carolina; Sabbione, Florencia; Geffner, Jorge; Salamone, Gabriela

doi:10.1111/all.12926

Cited by 35 publications

(43 citation statements)

References 34 publications

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“…Nevertheless, in our current system, the net effect of over-expressing nematode AChE during systemic infection of mice with our vehicle is polarisation to a Th1 environment and skewing of macrophages to an M1 phenotype. Other recent published work is consistent with this observation, as cholinergic stimulation of dendritic cells promotes production of IL-4, IL-5 and IL-13 in the course of a mixed lymphocyte reaction [36]. …”

Section: Discussionsupporting

confidence: 87%

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

et al. 2016

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Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host.

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Section: Discussionsupporting

confidence: 87%

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

et al. 2016

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“…Myeloid/classic DC, plasmacytoid DC, monocyte-related DC, and Langerhans cell subtypes exert divergent biological effects as antigen presenting cells, including differential capacity for cross presentation, 24 cytokine production, and polarization toward Th1, Th2, Th17, or regulatory T cell (Treg) immunophenotypes under the influence of various microbiological and biochemical stimuli 25, 26, 27, 28. Each of these alternative DC subtypes, including Langerhans cells,29, 30, 31 DCs derived from CD34-positive umbilical cord blood progenitor cells,32, 33, 34, 35 and plasmacytoid DCs36, 37, 38, 39 have been explored for use in DC vaccine development in different solid and hematologic malignancies.…”

Section: Main Textmentioning

confidence: 99%

Dendritic Cell Therapies for Hematologic Malignancies

Weinstock

Rosenblatt

Avigan

2017

Molecular Therapy - Methods & Clinical Development

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Dendritic cells (DCs) are potent antigen-presenting cells that constitute a major component of the immune system’s role in the recognition, elimination, and tolerance of cancer. The unique immunologic capabilities of DCs have recently been harnessed for therapeutic use with the creation of DC-based anti-tumor vaccines, several of which have moved into testing in clinical trials for hematologic malignancies. This review summarizes how treatment strategies using DC-based anti-tumor vaccines are advancing immunotherapeutic options for these diseases.

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“…However, the mechanisms underlying the effects of parasympathetic nerves on immune cells in patients with AR are not clear. Although increasing evidence indicates the importance of parasympathetic nerves in the immune function of patients with other systematic diseases, studies of neuroimmune regulation in the field of AR have rarely been reported , , . ‐ In the present study, by establishing an in‐vitro neuroimmune coculture model of D‐U87 neurons and CD4 + T cells, we observed that cholinergic neuron‐like D‐U87 cells promoted the polarization of CD4 + T cells from patients with AR toward Th2 cells, and inhibition of the cholinergic activity of D‐U87 cells by IB decreased the preferential Th2 polarization by modulating Akt signaling.…”

Section: Discussionmentioning

confidence: 47%

“…The components of the cholinergic system, including acetylcholine (ACh), muscarinic and nicotinic receptors, acetylcholinesterase, and choline acetyltransferase, were found to be expressed by T and B cells . Treatment of dendritic cells with ACh stimulated expression of the Th2‐promoter OX40L and the synthesis of interleukin (IL)‐4, IL‐5, and IL‐13 by T cells . ACh induced polarization of naive CD4 + T cells toward the Th1, Th2, and Th17 lineages by acting on cholinergic receptors .…”

mentioning

confidence: 99%

Cholinergic neuron‐like D‐U87 cells promote polarization of allergic rhinitis T‐helper 2 cells

Wang

Xia

et al. 2019

Int Forum Allergy Rhinol

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Background Parasympathetic nerve hypersensitivity contributes to the severity of allergic rhinitis (AR), but the precise mechanism underlying neuroimmune regulation in patients with AR remains unclear. This study investigated the effect of cholinergic nerve inhibition on AR CD4+ T‐helper (Th)2‐cell polarization and the underlying regulatory mechanism in vitro. Methods An in‐vitro neuroimmune coculture model of D‐U87 cells and CD4+ T cells was established. D‐U87 cells with cholinergic neuron characteristics were used as cholinergic neuron models. CD4+ T cells were derived from peripheral blood monocytes from AR patients (n = 60) and control subjects (n = 40). Th1‐ and Th2‐cell percentages were measured by flow cytometry. Proteins involved in related signaling pathways were analyzed by protein chip assay and Western blotting. Results The Th2‐cell percentage among CD4+ T cells from AR patients was significantly increased after coculture with D‐U87 cells and was decreased by ipratropium bromide (IB) treatment. In contrast, the Th1‐cell percentage among control CD4+ T cells was significantly increased after coculture with D‐U87 cells, but was unaltered by IB treatment. Furthermore, phosphorylated Akt (p‐Akt) protein levels increased in CD4+ T cells from both controls and AR patients after coculture with D‐U87 cells and decreased after IB treatment. However, higher p‐Akt levels were observed in cells from AR patients than in cells from control subjects. Moreover, Akt inhibition decreased Th2‐cell percentage in AR patients. Conclusion In‐vitro cholinergic nerve inhibition with IB decreased AR CD4+ T‐cell polarization into Th2 cells partially through an Akt‐dependent mechanism.

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Acetylcholine polarizes dendritic cells toward a Th2-promoting profile

Abstract: Our observations suggest that ACh polarizes DC toward a Th2-promoting profile.

Cited by 35 publications

References 34 publications

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

Dendritic Cell Therapies for Hematologic Malignancies

Cholinergic neuron‐like D‐U87 cells promote polarization of allergic rhinitis T‐helper 2 cells

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