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Disease-associated functions of IL-33: the new kid in the IL-1 family

Key Points

  • Interleukin-33 (IL-33) is a newly described member of the IL-1 cytokine family. IL-33 is expressed by endothelial cells, fibroblasts and neuronal cells.

  • The IL-33 receptor comprises ST2 and IL-1 receptor accessory protein and acts on various cell types, especially mast cells and T helper 2 (TH2) cells.

  • Full-length biologically active IL-33 is released by necrotic cells. When released by apoptotic cells, IL-33 is cleaved and inactivated by caspases.

  • IL-33 can protect mice against helminth and respiratory viral infections by preferentially activating TH2 cells.

  • Soluble ST2 could be a biomarker for myocardial infarction, and IL-33 administration decreased cardiac dysfunction and improved survival following atherosclerosis in mice.

  • However, IL-33 can also induce anaphylactic shock and allergic dermatitis in atopic patients and promote collagen-induced arthritis in mice by enhancing mast cell degranulation. IL-33 can also exacerbate experimental asthma by increasing TH2 cell activity.

  • A better understanding of the molecular mechanism of the action of IL-33 in various disease conditions might lead to its therapeutic targeting.

Abstract

Interleukin-33 (IL-33), a newly described member of the IL-1 family, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (TH2) cells and mast cells. IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting TH2-type immune responses. However, IL-33 can also promote the pathogenesis of asthma by expanding TH2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation. Thus IL-33 could be a new target for therapeutic intervention across a range of diseases.

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Figure 1: Interleukin-33 signalling pathways.
Figure 2: The role of interleukin-33 in asthma.
Figure 3: Schematic of the role of interleukin-33 in rheumatoid arthritis.

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Acknowledgements

We thank all our colleagues who contributed to the study of IL-33.

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Glossary

Atherosclerosis

A chronic disorder of the arterial wall characterized by endothelial cell damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.

Necrosis

A form of cell death that frequently results from toxic injury, hypoxia and stress. Necrosis involves the loss of cell membrane integrity and release of cell contents into the interstitium. This form of cell death usually occurs with inflammation. Depending on the context, the self antigens that are released by necrosis can become immunogenic.

Calpain

One of a group of Ca2+-activated cytoplasmic proteases that are found in many tissues and that hydrolyse various endogenous proteins, including neuropeptides and cytoskeletal proteins, as well as proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses are known: one with high Ca2+ sensitivity and one with low Ca2+ sensitivity.

Programmed cell death

A common form of cell death, which is also known as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Asthma

A chronic disease of the lungs, characterized by airway hyperresponsiveness and inflammation. The most common form of the disease, allergic asthma, results from inappropriate immune responses to common allergens in genetically susceptible individual's. Allergic asthma is characterized by infiltration of the airway wall with mast cells, lymphocytes and eosinophils. CD4+ T cells producing TH2-type cytokines are thought to have a pivotal role in orchestrating the recruitment and activation of these effector cells of the allergic response.

Alternatively activated macrophage

A macrophage stimulated by IL-4 or IL-13 that expresses arginase-1, mannose receptor CD206 and IL-4 receptor-α. There may be pathogen-associated molecular patterns expressed by helminths that can also drive the alternative activation of macrophages.

Anaphylaxis

A severe and rapid allergic response triggered by the activation of high-affinity Fc receptors for IgE in sensitized individuals. An anaphylactic shock is the most severe type of anaphylaxis and will usually lead to an individuals death in minutes if left untreated.

Atopic dermatitis

A chronic skin disease in which the skin becomes itchy and inflamed, causing redness, swelling, cracking, weeping, crusting and scaling. Its multifactorial pathogenesis involves genetic susceptibility, environmental triggers and immune dysregulation (typically dominated by TH2 cells), with the involvement of IgE contributing to its classification as an atopic disease.

Myocardial infarction

Acute cardiac ischaemia that leads to the death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.

Astrocyte

A type of glial cell that is found in vertebrate brain and is named owing to its characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, thereby regulating the environment in which they function.

Experimental autoimmune encephalomyelitis

An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

Alzheimer's disease

A degenerative neurological disease that is characterized by progressive deterioration of the brain, dementia and the presence of senile plaques, neurofibrillary tangles and neuropil threads. Disease onset can occur at any age, and women seem to be affected more frequently than men.

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Liew, F., Pitman, N. & McInnes, I. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol 10, 103–110 (2010). https://doi.org/10.1038/nri2692

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