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Therapeutic opportunities of the IL-22–IL-22R1 system

Nature Reviews Drug Discovery volume 13, pages 21–38 (2014)Cite this article

Subjects

Key Points

  • Interleukin-22 (IL-22) is a cytokine that is produced during inflammation by activated T cells, including T helper 22 (TH22), TH17 and TH1 cells, and by subsets of innate lymphoid cells (ILCs).

  • Via its transmembrane receptor complex composed of IL-22 receptor 1 (IL-22R1) and IL-10R2, IL-22 mainly influences epithelial cells, hepatocytes, pancreatic acinar cells and related stem cells.

  • In many of its target cells, IL-22 enhances the production of antibacterial proteins, inhibits their differentiation and/or increases their proliferation, and protects them against damage. Furthermore, it potentiates the tumour necrosis factor (TNF)- and IL-17-induced production of pro-inflammatory mediators.

  • Therapeutic strengthening of the IL-22–IL-22R system — for example, through the application of recombinant IL-22 or IL-22-inducing small molecules — might have a beneficial impact in liver and pancreas damage, ulcerative colitis, graft-versus-host disease and transplantation of IL-22R1-expressing organs.

  • Conversely, the regenerative and protective effects mediated via IL-22R1 might have a pathogenetic role in, for example, psoriasis and tumorigenesis of IL-22R1-expressing cancers, which suggests that attenuation of the IL22–IL-22R system might be beneficial in such situations.

  • Targeting IL-22R1 (for example, with antibodies) may produce better clinical results than IL-22 neutralization, because two other cytokines — IL-20 and IL-24 — are often co-produced during inflammation and can mediate IL-22-like effects in an IL-22R1-dependent manner.

  • Owing to the lack of IL-22R1 expression on haematopoietic cells, therapeutic modulation of the IL-22–IL-22R1 system is not expected to be accompanied by severe immunological side effects.

Abstract

Interleukin-22 (IL-22) is a key effector molecule that is produced by activated T cells, including T helper 22 (TH22) cells, TH17 cells and TH1 cells, as well as subsets of innate lymphoid cells. Although IL-22 can act synergistically with IL-17 or tumour necrosis factor, some important functions of IL-22 are unique to this cytokine. Data obtained over the past few years indicate that the IL-22–IL-22 receptor subunit 1 (IL-22R1) system has a high potential clinical relevance in psoriasis, ulcerative colitis, graft-versus-host disease, certain infections and tumours, as well as in liver and pancreas damage. This Review highlights current knowledge of the biology of the IL-22–IL-22R1 system, its role in inflammation, tissue protection, regeneration and antimicrobial defence, as well as the positive and potentially negative consequences of its therapeutic modulation.

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Figure 1: IL-22–IL-22R1 system and downstream signalling events.
Figure 2: Key effects of IL-22.
Figure 3: Role of the IL-22–IL-22R1 system in psoriasis.
Figure 4: Role of the IL-22–IL-22R1 system in the defence against intestinal infections.
Figure 5: Roles of the IL-22–IL-22R1 system in liver damage.
Figure 6: Options for therapeutic modulation of the IL-22–IL-22R1 system.

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Authors and Affiliations

  1. Department of Dermatology and Allergy, Interdisciplinary Group of Molecular Immunopathology, Institute of Medical Immunology, University Medicine Charité, Charitéplatz 1, Berlin, D-10117, Germany

    Robert Sabat & Kerstin Wolk

  2. Research Center Immunosciences, University Hospital Charité, Hessische Strasse 3–4, Berlin, D-10115, Germany

    Robert Sabat & Kerstin Wolk

  3. Department of Immunology, Genentech, 1 DNA Way, South San Francisco, 94080, California, USA

    Wenjun Ouyang

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  1. Robert Sabat
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Correspondence to Robert Sabat.

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W.O. is an employee of Genentech.

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Glossary

IL-10 cytokine family

A group of cytokines that, in humans, comprises interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24, IL-26 and the interferon-λ (IFNλ) species (IL-28α, IL-28β and IL-29).

Antibacterial proteins

Small proteins that are mainly produced by epithelial cells and phagocytes; these proteins kill or inhibit the growth of bacteria using different mechanisms, including pore formation in the bacterial membrane and sequestration of metal ions that are essential for bacterial growth.

Psoriasis

A chronic disease that is characterized by red, raised, sharply demarcated, scaling skin lesions that frequently occur on the scalp, the back and the extension side of the limbs. Lesions have infiltration of immune cells in the dermis and epidermis, and a massively altered epidermis structure.

Innate lymphoid cells

(ILCs). Immune cells that are characterized by lymphoid morphology, the absence of T cell and B cell receptors and a lack of myeloid cell surface markers. Based on their cytokine production profile, they are divided into three groups: group 1 cells (which have a profile similar to T helper 1 (TH1) cells), group 2 cells (which have a profile similar to TH2 cells) and group 3 cells (which have a profile similar to TH17 and TH22 cells).

Class 2 cytokine receptor family

A group of transmembrane receptor chains with extracellular domains composed of two tandem fibronectin type III domains that have conserved cysteine residues but that do not contain the Trp-Ser-X-Trp-Ser motif that is typical of the class 1cytokine receptor family.

Janus kinases

A group of tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) that are associated with the intracellular domains of the class I and class II family of cytokine receptors. By initiating phosphorylation steps, they transduce the signal that is generated from a receptor complex (following the binding of the cytokine to the receptor) to intracellular signal transducer and activator of transcription (STAT) molecules.

Mucus-associated proteins

A family of macromolecules composed of a central protein that is highly glycosylated. Glycosylation is associated with a very high water-binding capacity and protection from proteolysis. These molecules are produced by cells of the respiratory and intestinal tracts, where they form the mucus that protects the epithelial layer.

Acanthosis

Thickening of the stratum spinosum layer of the epidermis.

Parakeratosis

The presence of remnants of the cell nucleus in the epidermal stratum corneum, caused by dysfunction of the keratinocyte cornification process.

Acute-phase proteins

Plasma proteins, levels of which increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) during infection or inflammation owing to altered secretion — mostly by hepatocytes — in response to circulating cytokines.

Rheumatoid arthritis

A systemic autoimmune disease with a relapsing progressive course that begins with synovitis and leads to arthritis, tendovaginitis and substantial loss of function of affected joints.

Hepatitis

A group of liver disorders characterized by inflammation and the presence of immune cells within the organ. The persistent inflammation and immune cell attack on hepatocytes leads to hepatocyte injury, fibrosis and consequent loss of liver function.

Pancreatitis

A disorder of the pancreas that is characterized by intrapancreatic activation of digestive enzymes, immune cell infiltration and progressive destruction of the exocrine — and eventually also endocrine — tissue of this organ.

Atopic dermatitis

A chronic skin disease that is characterized by itchy, red and flaky lesions that often occur on bending sides of the limbs. The lesions have infiltration of immune cells in the dermis and epidermis as well as acanthosis, fibrosis and collagen deposition in the chronic stage.

Acne inversa

A chronic inflammatory disease that affects axillary, inguinal and perianal skin areas, leads to the development of inflamed nodules, abscesses and fistula, and is associated with painful tissue destruction, malodorous purulence and extensive scarring.

Crohn's disease

A chronic bowel disease — often located in the terminal ileum and proximal colon — that is characterized by an inflammation of all layers of the intestinal wall. Typical characteristics include ulcerations, crypt abscesses that have neutrophilic granulocytes, granuloma-containing macrophages and subserous lymphocyte aggregates.

Ulcerative colitis

A chronic bowel disease that mostly begins from the rectum and continuously spreads proximally. It usually affects the mucosa, which is infiltrated with lymphocytes and macrophages.

Asthma

The most common form of chronic inflammatory airway disease that is characterized by bronchial hyperresponsiveness and variable, recurring and reversible airflow obstructions.

Ovalbumin-induced asthma

A mouse model of human asthma. The repeated application of ovalbumin during the sensitization phase leads to the generation of ovalbumin-specific T helper cells. Lung inflammation is induced by subsequent intranasal application of ovalbumin (effector phase).

Citrobacter rodentium

A bacterium that induces acute colitis in mice. This infectious colitis is used as a murine model of human infection produced by attaching and effacing bacterial pathogens such as enterohaemorrhagic Escherichia coli and enteropathogenic E. coli, which cause diarrhoea, morbidity and mortality, especially among infants and children.

Rheumatoid factor

Autoantibodies against the Fc portion of an organism's own immunoglobulin G. Around 80% of patients suffering from rheumatoid arthritis have high levels of rheumatoid factor, whereas only 5% of healthy people have rheumatoid factor, and mostly at a low level.

Enthesitis

Inflammation at the sites where tendons or ligaments insert into the bone. Enthesitis is often associated with ankylosing spondylitis and psoriatic arthritis.

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Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nat Rev Drug Discov 13, 21–38 (2014). https://doi.org/10.1038/nrd4176

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