Research Progress on the Role of IL-33 in Autoimmune and Allergic Skin Diseases

IL-33 (Interleukin-33) is a new member of the IL-1 (Inter-leukin-1) family, and ST2 is its specific receptor. Endothelial cells, epithelial cells, macrophages, mast cells, and dendritic cells can all produce IL-33, which can induce Th2 type cytokine gene expression by binding to the specific receptor ST2 and promote Th2-mediated immune responses. Recent studies have shown that IL-33 acts as an inflammatory factor in some autoimmune diseases and inflammatory diseases. Some studies have shown that IL-33 has certain effects on the diagnosis and evaluation of diseases. This article reviews the research progress of the correlation between IL-33 and common autoimmune and allergic skin diseases.

1. Structure and function of IL-33

1.1 Structure of IL-33

In 2005, Schmitz et al. Found that IL-33 is related to IL-1 by digitizing the protein sequence in the IL-1 family cytokine database. IL-33 is a member of the IL-1 family, and its β-turn is a conserved structure unique to its C-terminal IL-1 family. The human IL-33 gene is located on chromosome 9 (9p24.1) and encodes an amino acid composed of 270 polypeptides with a molecular weight of approximately 30,000. 54% of the amino acid sequences are homologous to mice.

1.2 Function of IL-33

1.2.1 Secreting cells and receptors of IL-33

L-33 was once thought to be isolated from keratinocytes, epithelial cells, and endothelial cells, and it is now thought to be a pro-inflammatory factor that can be released by a variety of tissues. At the protein level, IL-33 is mainly secreted by epithelial cells and endothelial cells. Under appropriate stimulation, immune cells, macrophages, and dendritic cells can also produce IL-33. Antigen-associated molecular model molecules and some cytokines such as TNF-α, IL-1, IFN-γ can stimulate macrophages to secrete IL-33. As a warning factor, necrotic cells can secrete IL-33, and IL-33 is mainly secreted in endothelial and epithelial cells, which may play an important role in infection and inflammatory diseases. The ST2 molecule is a member of the IL-1 receptor family, and it includes two forms: mature membrane ST2 (ST2L) and soluble secreted ST2 (s ST2). ST2L is mainly expressed on the surface of natural killer cells, mast cells, monocytes, dendritic cells, granulocytes, and Th2 cells.

1.2.2 Mode of action of IL-33

IL-33 can function in the nucleus and extracellular parts, including two forms: precursor IL-33 (pro-IL-33) and mature IL-33 (matureIL-33, mtrIL-33). ProIL-33 is mainly located in the nucleus. When it is inflammatory or otherwise stimulated, proIL-33 is released and broken down into a smaller molecular weight mtrIL-33. Luzina et al believe that unlike mtrIL-33, proIL-33 can promote inflammation without relying on receptor ST2, while mtrIL-33 depends on receptor ST2. IL-33 can promote myeloid cells after binding to IL-33 receptor. Myeloid differentiation primary re-sponse protein 88 (My D88), IL-1 receptor-associated protease 1, and 4 recruited from the cytoplasmic ST2 receptor complex to induce nuclear factor-κB (NF-κB), External signal-regulated protease 1 and 2, p38, c-Jun and other protein signaling pathways activate, leading to the production of inflammatory mediators IL-1β, IL-3, IL-5, IL-6, IL-13, TNF, and promote Th2 cells Leading immune response.

2. Relationship between IL-33 and allergies and autoimmune skin diseases

2.1 Relationship between IL-33 and allergic diseases

2.1.1 Atopic dermatitis (AD)

AD is a chronic inflammatory disease. Classical Th2 cytokines such as IL-4, IL-5, and IL-13 are expressed in skin lesions in the acute phase of AD patients, and IFN-γ produced by Th1 cells in the chronic phase. IL-33 is a new member of the IL-1 family and is involved in Th2 cell-mediated immune responses. It is mainly expressed in barrier tissues such as skin, small intestine, and lung, and can activate Th2 cells, mast cells, and eosinophils to produce Th2 type cytokines. In recent years, studies have shown that IL-33 is a red flag for AD, and the expression of IL-33 is increased in patients with skin lesions. Injecting recombinant IL-33 into mouse skin resulted in infiltration of T cells, macrophages, and eosinophils, and at the same time stimulated the release of Th2 type cytokines, indicating that IL-33 plays an important role in Th2 cell-mediated immune responses. Compared with normal people, the serum level of IL-33 in AD patients was significantly increased, and it was positively correlated with the severity of skin lesions. Erythema, pimples, scabs, scratches, and lichenification are the most common types of skin lesions in AD patients. IL-33 is associated with scratches and dryness scores. After topical application of calcineurin inhibitors such as tacrolimus, the patient’s skin lesion severity score decreased significantly, and serum IL-33 levels decreased. It shows that IL-33 is related to the pathogenesis of AD. Mechanical damage and skin barrier dysfunction can lead to increased expression of keratinocytes, endothelial cells, and fibroblasts. The level of IL-33 in serum may be one of the severity of AD patients. Forecast indicators.

2.1.2 Chronic urticaria

Chronic urticaria is a common skin disease. Many cytokines are involved in the pathogenesis of chronic urticaria. Studies have shown that the expression of IL-33 in the skin lesion area is significantly increased compared with normal people and non-skinned skin. Some domestic scholars have detected serum IL-33 before and after treatment of chronic urticaria, and found that serum IL-33 levels in patients with chronic urticaria were significantly increased, which was positively correlated with the severity of the patient’s condition. After 4 weeks of treatment with loratadine, the serum IL-33 level did not decrease significantly. It is speculated that persistently high levels of IL-33 expression may be one of the reasons for the recurrence of chronic urticaria patients after discontinuation of antihistamines.

2.1.3 Allergic purpura

Allergic purpura is the most common vasculitis mediated by Ig A-associated immune complexes, but the molecular mechanism of its pathogenesis is unclear. Chen T et al found that the serum IL-33 level in patients with allergic purpura was significantly higher than that in the recovery period, and it was related to the severity of the disease and the serum Ig A anti-endothelial antibody. They speculated that the serum level of IL-33 in patients with allergic purpura is related to the production of Ig A antibodies in its pathogenesis.

2.2 Relationship between IL-33 and autoimmune diseases

2.2.1 Systemic lupus erythematosus (SLE)

Systemic lupus erythematosus is a complex chronic inflammatory autoimmune disease that causes a variety of tissue and organ damage. Cytokine-mediated immunity is involved in the pathogenesis of SLE and other autoimmune diseases. IL-33 is a pro-inflammatory factor and is considered a major effector molecule in SLE patients. Studies have pointed out that the level of IL-33 in serum of patients with SLE is elevated, and it is related to the severity of disease and kidney damage in patients with SLE. At the same time, Mok et al. Believe that compared with the normal group, the soluble receptor ST2 in the serum of patients with acute SLE is increased, which is positively related to the severity of the patient’s condition and is more sensitive to the treatment response. It could be a potential measure of disease severity. CRP, ESR, Ig A are closely related to IL-33 in the serum of SLE patients. It is well known that elevated levels of CRP and ESR indicate that patients with SLE are in the acute inflammatory phase, which indicates that IL-33 is related to the acute inflammatory phase in SLE patients.

2.2.2 Systemic sclero-sis (SSc)

SSc is a systemic connective tissue disease mainly manifested by sclerosis of the skin and internal organs, and is an autoimmune disease mainly mediated by Th2 cells. Manetti et al. Studied the effects of IL-33 and receptor ST2 in SSc and found that IL-33 and ST2 were abnormally expressed in SSc. Later, Yanaba et al. Found that compared with the healthy control group, the serum level of IL-33 in patients with SSc increased, and the level of IL-33 in the serum of patients with diffuse sclerosis was higher than that of patients with localized sclerosis. At the same time, pulmonary fibrosis also appeared in patients with elevated serum IL-33 levels. This suggests that IL-33 may be involved in the pathogenesis of SSc.

2.2.3 Pemphigus vlu-garis (PV)

PV is an acantholytic cell mediated by anti-desmogrin 3 and / or anti-desmogrin 1 autoantibodies. It is an autoimmune blister mainly manifested in skin and / or mucosal blister and erosion. Sexually transmitted diseases. The exact molecular mechanism of PV pathogenesis is still unclear, and abnormal cytokine signaling may be involved in the pathogenesis of PV patients. IL-33 and soluble ST2 play important roles in the regulation of inflammation, however, overexpression may cause autoimmune diseases. Some scholars have studied the role of IL-33 and ST2 in patients with PV, and explored the relationship between the serum level of IL-33 and the clinical severity of patients and the dose of hormone therapy. They found that serum levels of IL-33 in PV patients were significantly elevated and were positively correlated with the severity of the patient’s condition. The level of IL-33 in the serum of patients with prednisone with a skin area of ​​1 mg / kg / day was smaller than that in patients with 1 mg / kg / day. With treatment, the patient’s skin lesions improved and IL-33 levels decreased. This indicates that IL-33 may be involved in the occurrence of PV, which is related to the severity of the patient’s condition. The level of IL-33 is higher in those with a larger lesion area than in those with a smaller area, indicating that it can reflect the severity of inflammation. It is thought that IL-33 may promote the activation of Th2 cells by inducing the production of IL-6 and TNF-α, participate in the pathogenesis of PV, and affect the severity of the disease.

3. Summary and outlook of IL-33

As a pro-inflammatory factor, IL-33 plays an important role in chronic inflammatory diseases such as allergic reactions and autoimmune diseases. The IL-33 / ST2 pathway has been shown to participate in many different pathological processes. IL-33 and its receptor ST2 are potential therapeutic targets for allergic and autoimmune diseases. However, their specific mechanism in these diseases is still unclear.

Therefore, more genetic, immune and other related studies are needed to further study the structure of IL-33, ST2 and their functions and signaling pathways in these diseases, which may provide new ideas for the pathogenesis and treatment of these diseases.

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