Elsevier

Autoimmunity Reviews

Volume 13, Issues 4–5, April–May 2014, Pages 496-502
Autoimmunity Reviews

Review
The IL-23/IL-17 axis in psoriatic arthritis

https://doi.org/10.1016/j.autrev.2014.01.050Get rights and content

Abstract

Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease, affecting both the skin and joints. Disease progression is associated with aberrant cytokine expression, and TNF blockade is the most successful therapy to date. However, not all patients are responsive to anti-TNF treatment, highlighting the need to better understand the cellular and molecular mechanisms that govern the disease. PsA associations with single nucleotide polymorphisms in IL23R as well as TRAF3IP2 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to disease pathology. Although both cytokines are implicated in PsA, a full picture of their cellular targets and pathogenic mechanisms has not yet emerged. In this review, we focus on the IL-23/IL-17 axis-elicited responses mediated by osteoclasts, keratinocytes and neutrophils. Expanding our understanding of the cellular and molecular mechanisms that dictate pathogenicity in PsA will contribute to developing novel treatment strategies to combat disease.

Introduction

Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease affecting both the skin and joints in up to 1% of the worldwide population [1]. Psoriatic skin features commonly include epidermal hyperplasia (thickening of the epidermis), hyperkeratosis (thickening of the stratum corneum), parakeratosis (retention of nuclei in the stratum corneum), Munro's microabscesses (neutrophilic granulocytes in the epidermis) and mixed dermal infiltrates, including T cells, dendritic cells (DCs) and macrophages which together, lead to the clinical features of raised erythematous silvery plaques [2], [3]. In addition to the skin, PsA targets the spine, the peripheral joints and the entheses (attachment sites of ligament to bone) [4]. PsA can lead to destructive bone loss, and 67% of PsA patients exhibit signs of erosive bone disease [1]. Peripheral enthesitis is a feature of a group of arthritides known as spondyloarthropathies, which include PsA, but is not commonly observed in other forms of arthritis, such as rheumatoid arthritis (RA) [5]. Other distinguishing features of PsA include elevated numbers of neutrophils and CD163+ macrophages in the synovium and the presence of typical psoriasis nail lesions, not observed in RA [1], [6]. On the contrary, rheumatoid factor and anti-citrullinated peptide antibodies, which are commonly associated with RA, are not typically present in PsA [7], [8]. Despite the differences, increased numbers of osteoclasts have been observed in PsA synovium, similar to RA, suggesting that some molecular mechanisms that contribute to its pathogenicity are shared across these types of inflammatory arthritis [9]. Since osteoclast activation can be achieved through IL-23 and IL-17 as reviewed in [10], it is plausible that the IL-23/IL-17 axis may govern distinct cellular and molecular mechanisms that contribute to bone erosion and epidermal hyperplasia, hallmark features of PsA.

A variety of genetic, immunological and environmental factors have been suggested to contribute to PsA pathogenesis [11]. Single nucleotide polymorphisms in IL23A, IL23R as well as TRAF3IP2 (Act1), a downstream target of the IL-17 receptor (IL-17R), confer susceptibility to PsA, implying a central role of the IL-23/IL-17 axis in PsA disease pathogenesis [12], [13], [14]. In this review, we will address the contribution of the IL-23/IL-17 axis to PsA, with a specific emphasis on the activation of osteoclasts, which are responsible for bone degradation, and of keratinocytes and neutrophils, which have been implicated in IL-23/IL-17-induced PsA pathology.

Section snippets

IL-23 and IL-23 receptor

IL-23 is a heterodimeric cytokine, composed of a p19 subunit and a p40 subunit; it binds IL-23R and IL-12Rβ1, the latter being shared with IL-12 [15]. The p40 subunit can act as a monomer, homodimer or as a heterodimer with p19, and both subunits are secreted predominantly by macrophages and DCs [15]. Genetically engineered IL-23R GFP reporter mice have confirmed that IL-23R is expressed on the surface of lymphoid cells, such as αβ and γδ T cells, innate lymphoid cells and cells of myeloid

Neutrophils

The induction of NF-κB activation by the IL-23/IL-17 axis results in the production of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage stimulating factor (GM-CSF), and various chemokines (CXCL1, CXCL2, CXCL5 and CXCL8/IL-8) that in turn lead to the recruitment and migration of neutrophils [77], [78], [79]. IL-17 can stimulate endothelial expression of P-selectins, E-selectins and integrin ligands, including ICAM-1 and VCAM-1, to enhance neutrophil mobilization [80]. The

Conclusions

The role of IL-23 in inducing IL-17-producing T cells has been well studied; however, the importance of the IL-23/IL-17 axis in myeloid cell populations remains less understood. Nonetheless, sufficient progress has been made in understanding the role of the IL-23/IL-17 axis in psoriatic disease to support initiation of current clinical trials, which are evaluating the efficacy of IL-23 and IL-17 targeted therapy in psoriasis and PsA [109], [110]. More research is required to identify the

Disclosures

No conflict of interest disclosed.

Take-home messages

  • Single nucleotide polymorphisms in IL23R as well as TRAF3IP2, a target downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to PsA pathology.

  • The IL-23/IL-17 axis is a modulator of NF-κB activation in inflammation.

  • NF-κB activation is directly linked with osteoclastogenesis and epidermal hyperplasia, hallmark features of PsA.

Acknowledgments

We thank Thanh Nguyen for the help with graphic design. Research reported in this publication was partly supported by the NIAMS/NIH AR62173 and Shriners Hospitals for Children SHC 250862 to IEA. ES is the recipient of a NCATS/NIH #UR1 TR000002 pre-doctoral fellowship. EDM is partly supported by NIH R01AR061297. FON is partly supported by: EU FP7 grant agreement HEALTH-F2-2011-261366 and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas'

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