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Regulation of immune tolerance by anti-inflammatory neuropeptides

Key Points

  • The loss of immune tolerance results in the breakdown of immune homeostasis and the appearance of exacerbated inflammatory conditions and autoimmune diseases.

  • Several mechanisms act together to ensure self-tolerance, including clonal deletion, anergy, ignorance and exhaustion, effector T-cell and regulatory T-cell balance and cytokine deviation. Identifying factors that regulate these processes is crucial for the development of new therapies for inflammatory and autoimmune diseases.

  • Certain neuropeptides and hormones are produced in response to exacerbated inflammatory responses. Some of these neuropeptides, including the vasoactive intestinal peptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin and cortistatin, have emerged as endogenous anti-inflammatory factors that are involved in regulating immune tolerance, acting at several levels.

  • Anti-inflammatory neuropeptides bind to specific receptors that are expressed in immune cells, activate the cyclic AMP–protein kinase A pathway, and downregulate various transcription factors that are involved in the inflammatory response and in activating T cells.

  • These neuropeptides reduce the production of pro-inflammatory cytokines, chemokines and free radicals by macrophages, dendritic cells (DCs) and microglia, and inhibit the activation and differentiation of T helper 1 (TH1) cells.

  • These neuropeptides induce the emergence of regulatory T cells, especially under autoimmune conditions, involving several mechanisms. Neuropeptides directly induce the generation of CD4+CD25+ regulatory T cells in the periphery from the CD4+CD25 T-cell repertoire. In addition, neuropeptides generate tolerogenic DCs that have the capacity to induce interleukin-10-producing regulatory T cells.

  • The capacity of these neuropeptides to regulate the inflammatory response, the activation of autoreactive T cells and the generation of regulatory T cells, makes them attractive candidates for treating several inflammatory and autoimmune disorders. These neuropeptides are therapeutically beneficial in experimental models of sepsis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes.

  • Cellular therapies that are based on the use of regulatory T cells or tolerogenic DCs generated with neuropeptides are effective in treating various autoimmune diseases and transplantation.

Abstract

The induction of antigen-specific tolerance is essential to maintain immune homeostasis, control autoreactive T cells, prevent the onset of autoimmune diseases and achieve tolerance of transplants. Inflammation is a necessary process for eliminating pathogens, but can lead to serious deleterious effects in the host if left unchecked. Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology. In the last decade, various neuropeptides that are produced by immune cells with potent anti-inflammatory actions were found to participate in the maintenance of tolerance in different immunological disorders.

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Figure 1: Components of an autoimmune response.
Figure 2: Control of immune tolerance by VIP and α-MSH controls immune homeostasis.
Figure 3: VIP and α-MSH generate regulatory T cells.
Figure 4: Molecular mechanisms and transcription factors involved in the anti-inflammatory effect of neuropeptides.

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Acknowledgements

We thank the many researchers and laboratories that have contributed to our current understanding of the fundamental parts that neuropeptides play in immunology. This work was supported by grants from the Spanish Ministry of Health, the US National Institutes of Health and the Ramon Areces and La Caixa Foundations.

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Glossary

Neurotransmitter

A chemical that is used to relay, amplify and modulate electrical signals between a neuron and another cell. Common neurotransmitters include: amino acids, monoamines, acetylcholines, peptides (neuropeptides), purines and nitric oxide.

Co-stimulatory signal

A signal to a T cell (in the form of a soluble or membrane-bound molecule) that has little or no effect on its own, but either enhances or modifies the physiological effect of the primary signal mediated by engagement of the T-cell receptor.

G-protein-coupled receptor

A cell-surface protein of seven membrane-spanning domains that transduces an extracellular signal (ligand binding) into an intracellular cascade through the activation of a guanine nucleotide-binding protein (G protein). The neuropeptide receptors are all members of this family of proteins.

Microglia

Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are considered to be the brain-resident macrophages.

Chemokines

A family of small cytokines that are secreted by different cell types in response to bacterial or viral infections that induce directed chemotaxis in nearby responsive cells. Two major chemokine families are described: CC-chemokines with two adjacent cysteines near the amino terminus, and CXC-chemokines in which cysteines are separated by an amino acid.

Toll-like receptors

(TLRs). A family of receptors that recognize pathogen-associated molecular patterns. TLRs recognize conserved molecular patterns that are common to large groups of microorganisms and/or viruses.

Delayed-type hypersensitivity

A cellular immune response to antigen driven by T helper 1-type cytokines, which induce the infiltration and activation of T cells and macrophages over 24–72 hours.

Cytotoxic T-lymphocyte-associated protein 4

(CTLA4). A T-cell surface protein that, following its ligation to CD80 or CD86 on antigen-presenting cells, negatively signals activated T cells, inducing cell-cycle arrest and inhibiting cytokine production. CTLA4 is constitutively expressed by, and functionally associated with, regulatory T cells.

Alloreactive

The process of responding to antigens that are distinct between members of the same species, such as MHC molecules or blood-group antigens.

Catecholamine

A chemical compound derived from tyrosine that is mainly produced in the adrenal medulla and the postganglionic fibres of the sympathetic nervous system. The most abundant catecholamines are the biogenic amines adrenaline, noradrenaline and dopamine.

Hypothalamus–pituitary–adrenal axis

(HPA axis). A complex set of direct influences and feedback interactions between the paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that produce corticotropin-releasing hormone to stimulate the secretion of adrenocorticotropic hormone to the blood in the pituitary gland, which in turn stimulates the production of glucocorticoids in the adrenal cortex. The HPA axis is a major part of the neuroendocrine system, which controls reactions to stress and regulates digestion, energy usage, sexuality and the immune system (having an immunosuppressive action).

Septic shock

A systemic response to severe bacterial infections, which are generally caused by Gram-negative bacterial endotoxins, that leads to a hyperactive and out-of-balance network of inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance, and leads to tissue necrosis, multiple-organ failure and death.

Ghrelin

A hormone produced by the stomach that stimulates appetite and the secretion of growth hormone. It is considered to be the counterpart of leptin, which is produced by adipose tissue, and has been associated with anti-inflammatory actions.

Rheumatoid arthritis

An autoimmune disease that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone. It is divided into two main phases: initiation and establishment of autoimmunity to collagen-rich joint components, and later events associated with the evolving destructive inflammatory processes.

Crohn's disease

A chronic and relapsing inflammatory bowel disease that is characterized by dysfunction of mucosal T cells, altered cytokine production and cellular inflammation that ultimately leads to damage of the distal small intestine and the colonic mucosa, resulting in abdominal pain, rectal bleeding, diarrhoea and weight loss.

Experimental autoimmune encephalomyelitis

(EAE). An inflammatory demyelinating disease of the central nervous system, which shows pathological and clinical similarities to multiple sclerosis. EAE is considered to be an archetypal CD4+ T helper 1 cell (TH1 cell)-mediated autoimmune disease in which TH1 cells that are reactive to components of the myelin sheath infiltrate the nervous parenchyma, release inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

Graft-versus-tumour

An immune response mounted against tumour cells of an allogeneic bone-marrow transplant by donor T cells (mainly cytotoxic CD8+ T cells) that are derived from the graft.

Graft-versus-host disease

An immune response mounted against the recipient of an allograft (generally in the context of allogeneic bone-marrow transplantation) by donor T cells derived from the graft.

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Gonzalez-Rey, E., Chorny, A. & Delgado, M. Regulation of immune tolerance by anti-inflammatory neuropeptides. Nat Rev Immunol 7, 52–63 (2007). https://doi.org/10.1038/nri1984

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