Receptor signalling induces the activation of the adaptor protein ACT1, nuclear factor-κB (NF-κB) and tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which leads to increased transcription of the genes encoding IL-6 and IL-8. TNF is a homotrimer that acts on TNF receptor 1 (TNFR1) and TNFR2. The combination of IL-17 ligands and TNF often results in synergistic actions, which can be explained in part by increased mRNA stability and TNFR overexpression.

The effect of IL-17 on endothelial cells leads to inflammation and procoagulant activity. When acting on epithelial cells and fibroblasts, IL-17 leads to cytokine and enzyme production. On monocytes and dendritic cells, IL-17 contributes to inflammation by increasing the production of pro-inflammatory cytokines. In the context of joint inflammation, a process that involves osteoblasts and chondrocytes, IL-17 activates matrix destruction in cartilage and bone. CCL20, chemokine CC motif ligand 20; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage CSF; MMP, matrix metalloproteinase; RANKL, receptor activator of NF-κB ligand; T_H17, T helper 17; TNF, tumour necrosis factor.

Both IL-23 and IL-1 can further amplify TH17 cell differentiation. Fully differentiated TH17 cells express several effector cytokines. These include IL-17A, IL-17F, IL-22, IL-26 and granulocyte–macrophage colony-stimulating factor (GM-CSF). IL-17A and IL-17F signal through a complex made of IL-17 receptor A (IL-17RA) and IL-17RC chains. Signalling though these receptors induces the production of ligands for CXC chemokine receptor 2 (CXCR2) and granulocyte CSF (G-CSF). Activation through this pathway can augment cell proliferation and the expression of antimicrobial proteins. There are several sources of IL-17 that have been described to date, including T cells (γδ T cells and αβ T cells), innate lymphoid cells and natural killer (NK) cells.

Inhibitors of TH17 cell generation target retinoid-related orphan receptor-γ (RORC) as well as signal transducer and activator of transcription 3 (STAT3). AIN457 and LY2439821 are two monoclonal antibodies that target IL-17A, and AMG 837 is a monoclonal antibody that targets IL-17 receptor A (IL-17RA). In addition, there are other inhibitors of IL-17R-mediated signalling that act by blocking various different signalling events.

BAFF can be produced by two major sources: stromal cells and myeloid cells. BAFF can activate B cells via BAFF-R to activate ACT1. This results in the survival, proliferation, differentiation and regulation of class-switching recombination, leading to autoantibody production. In addition, BAFF can stimulate myeloid cells to produce IL-1β, IL-6, and IL-23. Moreover, BAFF can activate (memory) T cells, leading to increased expression of IL-6R. The myeloid-derived IL-1β, IL-6 and IL-23 can bind to their specific receptors on the stimulated (memory) T cells, inducing these cells to differentiate or activate into T_H17 cells. IL-6R and IL-23R activation on the activated T cells will trigger STAT3 phosphorylation and RORC expression, leading to induction of IL-17A, IL-17F and IL-23R expression. IL-17A and IL-17F can bind to their specific receptor and, via ACT1 and T_H17 cells, activate AP-1, NFκB and C/EBP. This activation results in enhanced expression of different chemokines and cytokines such as CXCL1, CXCL2, CXCL8, CCL2, CCL7, G-CSF and GM-CSF. Abbreviations: ACT1, nuclear factor NFκB activator 1; AP-1, activator protein 1; BAFF, B-cell-activating factor (also known as TNF ligand superfamily member 13B); BAFF-R, BAFF receptor (also known as TNF receptor superfamily member 13C); C/EBP, CCAAT/enhancer binding protein; CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-6R, IL-6 receptor; IL-17RA, IL-17 receptor subunit A; IL-17RC, IL-17 receptor subunit C; IL-23R, IL-23 receptor; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor κB; STAT3, signal transducer and activator of transcription 3; T_H17 cell, type 17 T helper cell; TRAF, TNF receptor associated factor; TYK2, non-receptor tyrosine-protein kinase TYK2.

These are hallmarks of diseases such as RA, psoriasis, PsA and SpA. T_H cells activated in the lymphoid organ migrate via the blood stream to the target organ, where they are involved in inducing or aggravating local tissue inflammation. In the joint, IL-17-producing cells including T_H17 and in particular the CD4⁺ memory CCR6⁺ T cell populations (see Figure 1) will produce T_H17-related cytokines such as IL-17A, IL-17F, IL-22 and IFN-γ. Direct cell–cell interaction as well as cytokine-driven activation of tissue-specific cells (FLSs, resident macrophages and myeloid cells) leads to a boost in cytokine production and activation of enzymes such as MMPs. In addition, T cell (in)dependent B-cell activation and T-cell-dependent B-cell terminal differentiation result in autoantibody production. This process creates an environment that leads to cartilage destruction by proinflammatory cytokines, IC-mediated effector pathways and MMPs, as well as bone erosion through osteoclast formation and activation. In the skin, the inflammatory process is driven by an influx of IL-17-producing cells, including T_H17 cells and T_H22 cells, and activation of keratinocytes by IL-23, IL-22, IL-17A and TNF. Enthesitis has been shown to be strongly IL-23-mediated, involving resident IL-23R⁺ T cells and IL-23-responsive cells, with IL-17A, IL-22 and IL-6 contributing to local inflammation. The extent of inflammation and, in particular, tissue destruction in these diseases could depend on whether the inflammation is more autoimmune or autoinflammatory by nature. The endocrine and neural systems might have a role in regulating the differentiation, migration and inflammation of these pathogenic T cells, although the mechanism is not understood. Abbreviations: CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; FcγR, Fcγ receptor; FLS, fibroblast-like synoviocyte; IC, immune complex; IL-23R, IL-23 receptor; MMP, matrix metalloproteinase; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor κB ligand; SpA, spondyloarthritis; T_FH cell, follicular helper T cell; T_H cell, T helper cell.

IL-17A is involved in the activation of different target cells. Autocrine IL-17A production induced by the interaction of CD4⁺ memory CCR6⁺ T cells and FLSs is mediated by the COX-2–PGE₂ pathway. IL-22 is a FLS-proliferation factor but also communicates with stromal cells to mediate terminal B-cell differentiation and production of autoantibodies that might be involved in osteoclastogenesis. RANKL is the key cytokine driving osteoclastogenesis and bone erosion. Most of the cytokines involved in bone erosion, such as IL-1β, TNF, IL-17, IL-22 and IL-23, act via activation of the RANKL–RANK–OPG system. Of note, osteoclasts can produce IL-23, which indirectly influences osteoclastogenesis via RANKL induction by T cells and might also contribute by activating pre-osteoclasts. The direct effects of IL-23 on osteoblasts are unknown. Abbreviations: ACPA, anti-citrullinated protein antibody; COX-2, cyclooxygenase 2; CXCL13, CXC-chemokine ligand 13; FLS, fibroblast-like synoviocyte; IL-22R, IL-22 receptor; MMP, matrix metalloproteinase; OPG, osteoprotegerin; PGE₂, prostaglandin E₂; RANK, receptor activator of nuclear factor κB; RANKL, RANK ligand.

RA is considered an autoimmune-mediated disease in which the IL-23–IL-17 pathway might be critical for the development of the disease; autoantibodies are essential and contribute substantially to disease severity. Cytokine-induced proinflammatory loops have a critical role in boosting the progression of RA including downstream antibody effector pathways which might become less IL-23/IL-17-dependent over the course of the disease. Potential flare-up of arthritis might be strongly IL-23/IL-17-mediated. In SpA, the discussion is ongoing as to whether AS, and potentially PsA, are autoinflammatory diseases with strong involvement of innate IL-23⁺/IL-17A⁺ cells. The interaction of these cells with different tissue-specific cells leads to aggressive inflammation involving activation of cytokine-mediated pathways that result in bone erosion and tissue remodelling. In PsA, involvement of both the skin and joints suggests that the disease pathogenesis might involve both autoimmune (joint) and auto-inflammatory (skin) types of inflammation, but this hypothesis requires further research. Abbreviations: AS, ankylosing spondylitis; FcγR, Fcγ receptor; IL-23R, IL-23 receptor; DC, dendritic cell; IC, immune complex; MMP, matrix metalloproteinase; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SNP, single nucleotide polypmorphism; SpA, spondyloarthritis; T_H17 cell, type 17 T helper cell; T_H22 cell, type 22 T helper cell; TLR, Toll-like receptor.