Interleukin-17 (IL-17) induces the production of granulocyte colony-stimulating factor (G-CSF) and chemokines such as CXCL1 and CXCL2 and is a cytokine that acts as an inflammation mediator. During infection, IL-17 is needed to eliminate extracellular bacteria and fungi, by inducing antimicrobial peptides such as defensin. This cytokine also plays an important role in chronic inflammation that occurs during the pathogenesis of autoimmune diseases and allergies such as human rheumatoid arthritis (RA) for which a mouse model of collagen-induced arthritis (CIA) is available. In autoimmune diseases such as RA and multiple sclerosis (MS), IL-17 is produced by helper T (Th) cells that are stimulated by IL-1
The immune system is a defense mechanism in the body that involves various types of blood cells derived from the bone marrow such as T cells and B cells, macrophages, and dendritic cells (DCs). The function of the immune system is to eliminate infectious microorganisms that have invaded the body and cancer cells that have been produced by mutations. The immune reaction leads to cell death under certain circumstances. Thus, excessive elimination of targets in chronic inflammatory reactions is harmful and is the cause of autoimmune diseases. Therefore, strict regulation is crucial to maintain immunological homeostasis. CD4-positive T cells, one type of T cell, are called helper T cells because they regulate the function of other immune cells. These helper T cells play a central role in the elimination of foreign microorganisms and in self-tolerance. Helper T cells produce cytokines that help activate immune cells in the microenvironment. IL-17 is an important cytokine not only for protective immunity against extracellular pathogens [
Various hematopoietic and lymphoid progenitors are mobilized from the bone marrow and initiate T cell development in the thymus. During this process, they express an antigen receptor (the T cell receptor, TCR), and most cells differentiate into CD4-positive T cells or CD8-positive T cells. After completion of the maturation process, CD8-positive T cells circulate throughout the body, acquiring cytotoxic functions. They contribute to immunological homeostasis by killing cells that have been infected by viruses as well as cancer cells. On the other hand, CD4-positive T cells are helper T cells. They exhibit an immunological regulatory function. Helper T cells have previously been divided into mainly two subsets (Figure
Regulation of Th cell differentiation. Naïve CD4 T cells differentiate into four distinct T cell subsets such as Th1, Th2, Th17, and induced T regulatory (Treg) cells dependent on the cytokine milieu.
IL-17 is a cytokine whose gene was isolated from a rat-mouse T cell hybridoma in 1993. Since it displayed a high degree of homology with the HVS13 Herpes virus gene, it was thought to be a subtype of the cytotoxic T-lymphocyte-associated protein (CTLA) family of proteins and called CTLA-8 [
IL-17 receptor A (IL-17RA) was identified as a new cytokine receptor for IL-17A and was found to be a member of the cytokine receptor family [
Adaptor protein Act1 and tumor necrosis factor receptor-associated factor (TRAF) regulate these molecular mechanisms after activation of IL-17R. Act1 was originally discovered as an NF-
IL-17-mediated mRNA stability of CXCL1 requires Act1 but not TRAF6, suggesting that Act1 mediates both TRAF6-dependent and TRAF6-independent pathways in IL-17R signaling [
Regulation of IL-17R pathways is important in the control of IL-17-mediated inflammation. As in intracellular mechanisms, fundamental features of inflammation have been revealed using mice lacking IL-17R subunits. IL-17RA-deficient fibroblasts failed to respond to IL-17A or IL-17F stimulation [
Central immune tolerance is the thymic mechanism that eliminates self-reactive T cell receptor-producing cells. However, the elimination is not perfect. Thus, self-reactive T cells exist in peripheral tissues. Peripheral immune tolerance refers to the suppression of self-reactive T cells by regulatory T cells. Failure of both types of tolerance may result in autoimmunity and autoimmune diseases. In autoimmune diseases, the helper T cells that support the acquired immunity system attack tissues in an antigen-specific manner. Tissue dysfunction accompanied by localized organ damage induced by self-reactive T cells leads to diseases. In human diseases, it is difficult to identify antigens and the causes of disease. Thus, methods using mouse models of these diseases, in which the disease can be induced by the identified antigens, are often used as a strategy for studying autoimmune diseases. For example, the CIA model is often used as a model for human RA, and the EAE mouse model is often used as a model for human MS. Currently, Th17 cells have been established as having a close relationship with chronic inflammatory autoimmune diseases. In this section, the first half introduces the current knowledge on inflammatory cytokines related to Th17 cells in autoimmune diseases based on results obtained using the EAE mouse model, and the second half briefly explains the role of Th17 cells and IL-17 in RA and psoriasis.
MS is an autoimmune disease accompanied by chronic neuroinflammation that causes demyelination in the CNS. Accumulation of helper T cells is observed in the cerebrospinal fluid of patients. The EAE mouse model that recapitulates MS is an experimental system in which pathogenic helper T cells can be induced by administering antigens in the CNS tissue, resulting in limb paralysis. The pathophysiological analysis of EAE is useful for understanding MS. MS-related genes have been proposed by establishing and screening the disease-related genome analysis (genome-wide association studies, GWAS) database [
Since Th1 cells strengthen cellular immunity and are present in chronic CNS inflammation [
After the discovery of the IL-23-Th17 axis, the properties of helper T cells were analyzed in detail. Th17 cells express RAR related orphan receptor
Mice lacking p19 display resistance to autoimmune diseases and a reduction in Th17 cells, so the importance of IL-23 as a differentiation factor is established. However, IL-23 cannot induce naïve T cells into mature Th17 cells. Additionally, naïve T cells do not express IL-23R. These results suggested that the priming stage of Th17 cell differentiation was regulated by other factors. Multiple groups showed that, in mice, the induction of Th17 cells is possible through simultaneous stimulation with transforming growth factor (TGF)
Helper T cells that induce major tissue damage are closely related to severe autoimmune diseases. Thus, the types of factors necessary for the maturation stages after the initial priming processes were investigated. IL-23, said to be necessary for Th17 cell induction, and its contribution to the production of inflammatory cytokines that are found in autoimmune diseases such as EAE (MS) and CIA (RA) garnered the attention again. Studies using mice lacking IL-23 indicated that helper T cells, whose IL-23 signals are blocked, undergo an early differentiation process of Th17 cells producing ROR
As described above, from many analyses, TGF
Blood cells in the CNS, including cells responsible for immunity as well as many blood proteins cannot pass through the blood-brain barrier (BBB) that strictly limits the flow of substances like proteins and cells from the bloodstream into the CNS. Cell migration and the transfer of the necessary proteins (nutrients) from the blood into the CNS are performed in an active way. This machinery requires energy. The structure of the BBB includes vascular endothelial cells that are strongly joined by tight junctions and various types of underlying cells such as pericytes, astrocytes, and microglia [
The chemokines that are produced at L5, the entry site of immune cells, include CCL21. Alt et al. presented a model in which pathogenic T cells infiltrate the CNS in a manner dependent on CCR7, the receptor for CCL21. They reported that the CCL21-CCR7 signal is necessary for EAE [
As for MS and EAE, Th17 cells strongly contribute to RA. Since Th17 cells cannot be separated from RA and MS disease conditions, the role and function of IL-17 have been analyzed in detail. The important clinical issue for RA is bone and joint destruction. Since bone destruction is directly related to changes in the joint structure, treatment for prevention of joint destruction is very important. Osteoclasts are the only cells that break down the bone, and they are a specially differentiated type of macrophage. Osteoclasts differentiate from monocytes, and receptor activator of nuclear factor kappa-B ligand (RANKL) promotes this process [
Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of epidermal cells. Pronounced acanthosis and inflammatory infiltration such as of neutrophils and lymphocytes are observed in lesions. As cyclosporin, a calcineurin inhibitor, shows therapeutic effectiveness, it is thought that T cells contribute to psoriasis pathology. Recent studies clarified that Th17 cells contribute to the onset of psoriasis [
In chronic inflammation, IL-23 stimulation confers higher pathogenicity on Th17 cells, and, in this process, not just IL-17, but also IFN
Based on research results using GWAS and animal models, clinical trials have begun, targeting either IL-23, which contributes to the final differentiation and function acquisition of pathogenic Th17 cells, or ROR
Tools for targeting the Il-23-Th17 axis. Various therapeutic tools are available to target the interlukin-23-Th17 pathway. Ustekinumab and briakinumab are two monoclonal antibodies that target p40, and tildrakizumab and guselkumab are monoclonal antibodies that target p19. Inhibitors of Th17 cell generation target RORgt. Ixekizumab and secukinumab are monoclonal antibodies that target IL-17, and brodalumab is a monoclonal antibody that targets IL-17 receptor A.
Screening tests are being performed to identify small molecules regulating the functions of Th17 cells. Among molecules that contribute to the maturation and function of Th17 cells, ROR
In this review, we discussed IL-17 and related cytokines in chronic autoimmune diseases. Since the discovery of IL-17, there have been many reports that Th17 cells are important in human and mouse chronic autoimmune diseases. While Th17 cells and IL-17 directly lead to the worsening of RA disease conditions, they are important factors that can be targeted to alleviate diseases. There is hope that molecular therapy targeting IL-23 or the master transcription factor ROR
Blood-brain barrier
Cluster of differentiation
Collagen-induced arthritis
Central nervous system
Cytotoxic T-lymphocyte-associated protein
Experimental autoimmune encephalomyelitis
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor
Genome-wide association studies
Interferon
Immunoglobulin
Interleukin
Major histocompatibility complex
Multiple sclerosis
Mammalian target of rapamycin (mechanistic target of rapamycin)
Rheumatoid arthritis
Receptor activator of nuclear factor kappa-B ligand
RAR related orphan receptor
Signal transducers and activators of transcription
Transforming growth factor
Helper T.
The authors have no financial conflict of interests.
This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research to Taku Kuwabara (25460600) and by a grant from Takeda Science Foundation to Taku Kuwabara. The authors would like to thank Editage (