Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

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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.

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