Superior Cervical Ganglia Neurons Induce Foxp3+ Regulatory T Cells via Calcitonin Gene-Related Peptide

Szklany, Kirsten; Ruiter, Evelyn; Mian, Firoz; Kunze, Wolfgang; Bienenstock, John; Forsythe, Paul; Karimi, Khalil

doi:10.1371/journal.pone.0152443

Cited by 10 publications

(9 citation statements)

References 73 publications

(74 reference statements)

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“…In addition to this neuronal transmission role, activated nociceptors release these neurotransmitters and neuropeptides at their peripheral endings, regulating activity of local immune cells including T cells. T cells express inotropic and metabotropic glutamate receptors, SP and CGRP receptors (Rameshwar et al, 1992; Ganor et al, 2003; Mikami et al, 2011; Ohtake et al, 2015; Szklany et al, 2016). Activation of these receptors regulates various T cell functions such as adhesion, chemotactic migration, proliferation and immunological phenotypes (Hosoi et al, 1993; Levite et al, 1998; Hood et al, 2000; Levite, 2000; Talme et al, 2008; Mikami et al, 2011).…”

Section: T Cells In Neuroimmune Interactionsmentioning

confidence: 99%

T Cells as an Emerging Target for Chronic Pain Therapy

Laumet

Robison

et al. 2019

Front. Mol. Neurosci.

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The immune system is critically involved in the development and maintenance of chronic pain. However, T cells, one of the main regulators of the immune response, have only recently become a focus of investigations on chronic pain pathophysiology. Emerging clinical data suggest that patients with chronic pain have a different phenotypic profile of circulating T cells compared to controls. At the preclinical level, findings on the function of T cells are mixed and differ between nerve injury, chemotherapy, and inflammatory models of persistent pain. Depending on the type of injury, the subset of T cells and the sex of the animal, T cells may contribute to the onset and/or the resolution of pain, underlining T cells as a major player in the transition from acute to chronic pain. Specific T cell subsets release mediators such as cytokines and endogenous opioid peptides that can promote, suppress, or even resolve pain. Inhibiting the pain-promoting functions of T cells and/or enhancing the beneficial effects of pro-resolution T cells may offer new disease-modifying strategies for the treatment of chronic pain, a critical need in view of the current opioid crisis.

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Section: T Cells In Neuroimmune Interactionsmentioning

confidence: 99%

T Cells as an Emerging Target for Chronic Pain Therapy

Laumet

Robison

et al. 2019

Front. Mol. Neurosci.

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“…We postulate that M1 and M3 may participate in the Th2 polarization process in cells from patients with AR. However, Th1 polarization appears to be more closely related to nonmuscarinic receptors based on the following reasons: (1) the stimulation of M1 and M3 inhibits secretion of the Th1 cytokine IFN‐γ, and the stimulation of nicotinic receptor increases the level of IFN‐γ; and (2) the β 2 ‐adrenergic receptor contributes to Th1 polarization, and activation of the calcitonin gene‒related peptide (CGRP) receptor contributes to T‐regulatory‐cell polarization, which promotes Th1 polarization . These findings indicate that D‐U87 cells could induce T cells from healthy individuals to polarize into Th1 cells by activating CGRP or nicotinic receptors, but not muscarinic receptors, because the addition of IB had no effect on this process.…”

Section: Discussionmentioning

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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“…This neurotransmitter appears to work by preventing the development of T-cell driven autoimmune responses, as occurs in Sjögren’s Syndrome. Like in superior cervical ganglia neurons, CGRP works to increase TGF-β to produce regulatory T cells that dampen inflammation [ 25 ]. TSP-1 activates TGF-β to prevent inflammation in the ocular surface tissues.…”

Section: Discussionmentioning

confidence: 99%

Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves

Tatematsu

Khan

Blanco

et al. 2018

IJMS

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Thrombospondin-1-deficient (TSP-1−/−) mice are used as an animal model of Sjögren’s Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren’s Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1−/− and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1−/− compared to WT mice, but tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1−/− mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1−/− compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1−/− mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1−/− mice age.

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Superior Cervical Ganglia Neurons Induce Foxp3+ Regulatory T Cells via Calcitonin Gene-Related Peptide

Cited by 10 publications

References 73 publications

T Cells as an Emerging Target for Chronic Pain Therapy

T Cells as an Emerging Target for Chronic Pain Therapy

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

Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves

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