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Interleukin-17 in inflammatory skin disorders
What is interleukin-17?
Interleukin (IL)-17 refers to a family of proteins that play critical roles against bacterial infections and fungal infections and in the pathogenesis of autoimmune diseases.
The IL-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). The interleukins 17A, 17F, and 17A/F heterodimer ligands share a common receptor subunit (interleukin-17RA) for signalling.
IL-17 is mainly produced by a subset of CD4 cells named Th-17 (T–helper 17) cells. It is mainly secreted by activated CD4+ and CD8+ T lymphocytes, while its receptor is found on many cell types.
What is the interleukin-17 pathway?
IL-17 has been classified as a pro-inflammatory cytokine because it induces the expression of mediators of inflammation involved in the proliferation, maturation, and chemotaxis of neutrophils.
- IL-17A and IL-17F are protective against infections on the epithelial surfaces of the skin, lung, and oral cavity [1,2]
- Signalling downstream of IL-17RA/RC elicits the expression of antimicrobial peptides (AMPs), including beta-defensins
- IL-17 acts with IL-22 (produced mainly by T-helper 22 cells in humans) to induce expression of AMPs by keratinocytes [3]
- IL-17A and IL-17F induce cytokines such as:
- Interleukin (IL)-6
- G-CSF (granulocyte colony-stimulating factor)
- GM-CSF (granulocyte-macrophage colony-stimulating factor)
- IL-1β (interleukin 1 beta)
- TGF-β (transforming growth factor-beta)
- TNF-α (tumour necrosis factor-alpha)
- Chemokines, such as IL-8
- Prostaglandins, such as PGE2
- Matrix metalloproteinases (MMP) [3].
Overproduction of interleukins 17A, 17F, and 17A/F is associated with tissue damage and autoimmune diseases such as:
- Rheumatoid arthritis (RA)
- Multiple sclerosis (MS)
- Crohn disease
- Systemic lupus erythematosus (SLE)
- Inflammatory skin diseases such as:
Skin diseases associated with interleukin-17
What is the protective role of interleukin-17 against infections?
The IL-17 family of cytokines play a role in the management of pathogens.
- IL-17F, IL-17A, and IL-17C are important for protection against Staphylococcus aureus (a cause of impetigo) and Candida albicans at epithelial surfaces [5].
- Therapies that block IL-17A and IL-17RA signals have the potential to exacerbate bacterial and fungal infections [6].
The same cytokines have also been reported to have functions outside the skin, at least trials involving mice. IL-17E has a protective role in CNS inflammation and participates in protective responses against parasites in the intestine [7–9].
Infections protected by IL-17
What skin diseases involve interleukin-17?
Skin diseases in which interleukin-17 is involved or is thought to be involved are as follows.
Psoriasis
Psoriasis is a chronic inflammatory skin condition characterised by epidermal hyperplasia.
- Elevated IL-17A and Th17-related cytokines, such as IL-22 and IL-23, are found in psoriatic plaques.
- The IL-17A-blocking monoclonal antibodies secukinumab and ixekizumab and the IL-17RA-targeting antibody brodalumab result in marked improvement and sometimes complete clearance of psoriasis [10–12].
- Several other molecules targeting the IL-17 family are in clinical development (eg, bimekizumab, which targets IL-17A and IL-17F), as are drugs targeting IL-23, which is upstream of IL-17, and signalling molecules, which are downstream [13,14].
Psoriasis
Dermatitis
The role of IL-17 is under investigation in various forms of dermatitis.
- Serum levels of IL-17A and F are increased in children with atopic dermatitis and are correlated with disease severity.
- Expression of IL-17A at the mRNA level is increased in the skin of patients with allergic contact dermatitis due to nickel allergy [15].
Skin cancer
IL-17 signalling has been associated with the development of skin cancer during chemical carcinogenesis in mouse models.
- This pro-tumourigenic effect of IL-17 is thought to occur via the promotion of epithelial proliferation and the anti-apoptotic effect of the transcription factor STAT-3 (Signal Transducer and Activator of Transcription 3), which may be downstream of IL-17-induced genes such as IL-6.
- IL-17A blockade may prove useful for controlling at least some cancers [16]. This is unproven in humans
Epithelial skin cancers
What are the future indications of the study of interleukin-17?
The proinflammatory properties of IL-17 are protective against infection. A good understanding of the different roles played by the IL-17 cytokines is necessary to design effective drugs relating to pathogenesis and mechanisms of inflammation.
- Unrestrained IL-17 signalling is associated with immunopathology, autoimmune disease, and cancer progression.
- IL-17 inhibitors are proving valuable in the control of inflammatory skin disease.
- Analysis of the roles of individual components of the IL-17 pathway in infection and inflammation is ongoing.
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References
- Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, et al. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 2001; 25: 335–40. PubMed
- Dubin PJ, Martz A, Eisenstatt JR, Fox MD, Logar A, Kolls JK. Interleukin-23-mediated inflammation in Pseudomonas aeruginosa pulmonary infection. Infect Immun 2012; 80: 398–409. PubMed
- Sheng, F and Gaffan SL. Structure-function relationships in the IL-17 receptor: Implications for signal transduction and therapy. Cytokine 2008; 41: 92–104. PubMed Central
- Monin L, Gaffan SL IL-17 family cytokines: signaling mechanisms, biological activities and therapeutic implications. Cold Spring Harb Perspect Biol 2018; 10: a028522. PubMed
- Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, Dong C. Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol 2012; 189: 4226–30. PubMed
- Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009; 30: 108–19. PubMed
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- Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; 386: 541–51. DOI: 10.1016/S0140-6736(15)60125-8. PubMed
- Papp KA, Langley RG, Sigurgeirsson B, Abe M, Baker DR, Konno P, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol 2013; 168: 412–21. PubMed
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