Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight - PubMed (original) (raw)

Review

Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight

Cuong Thach Nguyen et al. Clin Immunol. 2019 Sep.

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.

Keywords: Cytokines; Human monoclonal IL-23 antibodies; IL-23/IL-23R pathways; Psoriatic arthritis; Skin and joint inflammation; Therapeutics.

Copyright © 2018 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Conflict of interest

IEA has received grants, salary, consulting fees from Schering Plough Biopharma/Merck, Novartis, Pfizer and Tanabe Research Labs USA. The authors have no other conflicts of interest to declare.

Figures

Figure 1.

Figure 1.. Cellular pathophysiology of PsA.

In PsA, Th17, γδT cells, neutrophils, keratinocytes, and osteoclast are involved in the initiation of the disease. 1) Th17 cells activated by STAT3 lead to the release of IL-17, IL-21, IL-22, TNF, IFNγ and RANKL. 2) γδT cells are also activated by STAT3 to release of IL-17, M-CSF, CCL5, and CCL3. 3) In neutrophils, IL-23 induces the expression of IL-23R, and a number of transcriptional activators including STAT3-dependent RORγt, NF-κB, aryl-hydrocarbon receptor (AhR), mammalian target of rapamycin (mTOR) and Basic Leucine Zipper ATF-Like Transcription Factor (BATF) pathways that regulate IL-17A, IL-17F and IL-22. NETs, IL-1β and IL-8 also contribute to neutrophil activity in psoriasis. 4) In keratinocytes, the transcription factor Nrf2 promotes proliferation of keratinocyte through controlling expression of K6, K16, and K17. IL-23 induces directly and/or indirectly (IL-17/IL-22) the expression of K16/Ki67 or S100A7–9 leads to induce proliferation of keratinocytes, hyperplasia, and skin inflammation. 5) In osteoclasts, IL-23 induces the expansion of osteoclast precursors and activates NFATc1 leading to the expression of TRAP, CatK, MMP9 that facilitate bone resorption.

Figure 2.

Figure 2.. Schematic representation of the assembly mechanism of the IL-23-mediated receptor complex.

(A) The signaling complex mediated by IL-23 proceeds via the sequential recruitment of the two cognate receptors and involves conformational selection and restructuring of IL-23 (blue and green) by IL-23R (orange) to recruit IL-12Rβ1 (black and white) with high affinity (Bloch et. al., 2018, modified). (B) Cartoon representation of the crystal structure of the IL-23:IL-23R complex (PDB 5mzv).

Figure 3

Figure 3. Various antagonists developed to neutralize IL-23.

A) Crystal structure of the IL-23 in complex with neutralizing 7G10 Fab (PDB 3D85), B) Structure of Adnectin 2, an Adnectin recognizing IL-23 (PDB 3qwr), C) Structure of MA12, an Alphabody recognizing IL-23p19 (PDB 5mj4), D) binding epitope of human antibody AMG139 mapped onto the IL-23 structure, E) Structure of briakinumab Fab, an IgG1 antibody recognizing IL-12p40 (PDB 5n2k), F) binding epitope of a recombinant mouse anti-IL23 antibody CNTO 4088 mapped onto the IL-23 structure, G) human IL-23 in complex with three nanobodies (PDB: 4grw) H) binding epitope of a humanized murine mAb Risankizumab targeting IL-23p19, mapped onto the IL-23 structure I) binding epitope of a humanized anti-IL23p19 mAb Tildrakizumab, mapped onto the IL-23 structure J) Structure of Ustekinumab-Fab, human monoclonal antibody recognizing IL-12p40 (PDB: 3hmx). In green: IL-12p40, in blue: IL-23p19, IL-23 antagonists are depicted in pink and orange surface representations.

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