tand γ www.eji-journal.eu HIGHLIGHTS Eur. J. Immunol. 2018. 48: 220–229 Osteoclasts r 1,2 In recent years, it has become clear that the IL-23/Th17 path- them to migrate toward siteschemokine of CCL20 [8, inflammation 9]. in response to the way plays adiseases crucial including role psoriasis,toid in psoriatic arthritis many arthritis (RA) inflammatory (PsA), andBoth RA autoimmune rheuma- systemic and lupus PsA are erythematosus disorders [10–12]. with distinct clinical phenotypes, IL-23 drives their pathogenic phenotypeTh17 [4, cells 5]. are These characterized pathogenic by theirproduction master of regulator pro-inflammatory ROR cytokines such asIL-22, IL-17A, GM-CSF IL-17F, and arement able through to autocrine promotethese IL-21 cells their production express lineage [6, the commit- chemokine 7]. receptor Furthermore, CCR6, which enables Osteoblasts r DOI: 10.1002/eji.201646787 published by WILEY-VCH Verlag GmbH & Co. and Erik Lubberts 3 in complex with α Joint damage r IL-23 r European Journal of Immunology , Marjolein van Driel 1,2 Dr. Erik Lubberts Auto-immune arthritis 1, which also serves as a subunit for the IL-12 receptor [2]. β 2017 The Authors. The Netherlands Department of Immunology, Erasmus MC,The University Netherlands Medical Center, Rotterdam, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Department of Rheumatology, Erasmus MC,The University Netherlands Medical Center, Rotterdam, C of amplifying and stabilizingT the helper-17 proliferation (Th17) of IL-17 cells secreting [3]. In fact, exposure of Th17 cells to IL-12R Although structurally similar to IL-12, IL-23 has the unique ability is properly cited and is not used for commercial purposes. KGaA, Weinheim. This is an openLicense, access which article permits under use, the distribution terms and of reproduction the in Creative any Commons medium, provided Attribution-NonCommercial the original work Correspondence: e-mail: [email protected] [1]. The receptor for IL-23 consists of IL-23R Interleukin-23 (IL-23), aily, member is of a heterodimericsubunit, the cytokine, shared IL-12 which with cytokine consists IL-12, of fam- and an an IL-12p40 IL-23 specific p19 subunit Introduction Keywords: inflammation-mediated joint damage andthe bone clinical remodeling. implications At of last,loss targeting in we this autoimmune briefly arthritis. pathway discuss for joint damage and systemic bone a role in physiologicalautoimmune bone arthritis remodeling. in In patients this and review,producing murine we and models, focus responding and on cells provide thethe in an role role autoimmune overview of of arthritic of IL-23 IL-23 joints. IL-23 in on In bone addition, forming we osteoblasts discuss and bone resorbing osteoclasts regarding sive joint damage. IL-23 can act eitherwell directly or as indirectly on on bone bone forming resorbing osteoblastsit osteoclasts. as is As conceivable IL-23 that regulates in the addition activity to of inflammation-mediated cells joint of erosion, the IL-23 bone, may play such as rheumatoid arthritis (RA)neous and diseases with psoriatic substantial arthritis burden on (PsA). patients.IL-23 Increasing RA evidence signaling and suggests that pathway PsA the may are be heteroge- involved in the development of autoimmunity and ero- The IL-23/Th17 axis has been implicated in the development of autoimmune diseases, 2 3 1 and bone remodeling Wida Razawy inflammation-mediated erosive autoimmune arthritis The role of IL-23 receptor signaling in Wida Razawy et al. REVIEW
220 Clinical Eur. J. Immunol. 2018. 48: 220–229 HIGHLIGHTS 221
Table 1. An overview of studies on IL-23R polymorphisms in RA
IL-23R SNP Association Study population Number of Number of Study reference with RA patients controls rs1004819 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] No New Zealand 855 557 Hollis-Moffatt et al. [27] rs7517847 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] No New Zealand 855 557 Hollis-Moffatt et al. [27] rs10489629 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] No New Zealand 855 557 Hollis-Moffatt et al. [27] No Algerian 343 323 Louahchi et al. [20] rs11209026 No Spanish 322 342 Orozco et al. [26] No New Zealand 855 557 Hollis-Moffatt et al. [27] No North American 1136 1797 Chang et al. [21] No Dutch 596 705 Chang et al. [21] Yes Egyptian 120 120 Hamdy et al. [22] No Polish 89 125 Bogunia-Kubik et al. [25] No Algerian 343 323 Louahchi et al. [20] rs1343151 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] No New Zealand 855 557 Hollis-Moffatt et al. [27] No Algerian 343 323 Louahchi et al. [20] rs10889677 No Spanish 322 342 Orozco et al. [26] Yes Hungarian 412 220 Farago´ et al. [23] Yes Brazilian 127 134 Da Silva et al. [24] No Egyptian 120 120 Hamdy et al. [22] rs11209032 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] rs1495965 No Spanish 322 342 Orozco et al. [26] No Korean 1204 979 Park et al. [19] rs2201841 No Korean 1204 979 Park et al. [19] No New Zealand 855 557 Hollis-Moffatt et al. [27] Yes Hungarian 412 220 Farago´ et al. [23] No Egyptian 120 120 Hamdy et al. [22] rs7530511 No North American 1136 1797 Chang et al. [21] No Dutch 596 705 Chang et al. [21] rs1884444 No Hungarian 412 220 Farago´ et al. [23]
Meta-analyses are not included.
resulting from complex interactions between genetic and environ- as demonstrated by clinical studies where targeting IL-23 has dif- mental factors such as smoking or infections. Although there are ferent outcomes [14, 15]. In PsA, treatment with anti-IL-23 anti- some similarities between RA and PsA including the occurrence of bodies have shown beneficial effects but not in RA so far. Another erosive joint inflammation and systemic bone loss, there are also finding supporting this hypothesis, is the notion that polymor- important differences [13]. For instance, PsA displays features of phisms in the IL-23 receptor (IL-23R) have been linked to sus- spondyloarthropathy such as new bone formation and enthesitis, ceptibility for psoriasis and PsA [16–18], but are still a matter of while RA does not. Furthermore, both diseases affect different debate in RA (Table 1) [19–27]. anatomical joints and in addition to the joint, PsA targets the skin, In this review, we focus on the role of IL-23 in the development eyes and the spine [13]. of autoimmune arthritis and give an outline of IL-23 producing and Another difference is the occurrence of autoantibodies such responding cells in arthritic joints. In addition, we review on the as rheumatoid factor and anti-citrullinated protein antibodies role of IL-23 on bone forming and bone resorbing cells in relation (ACPAs), which are specific to RA, but not to PsA. Although the to erosive joint damage and bone remodeling. At last, we discuss IL-23 signaling pathway is implicated in both RA and PsA, its the implications of targeting the IL-23 signaling pathway for joint involvement in the pathogenesis of these disorders may be diverse damage and systemic bone loss.