Abstract and Introduction
The interleukin (IL)-1 family of cytokines is a central regulator of a myriad of immunological responses. It comprises several cytokines, including those belonging to the IL-1, IL-36 and IL-18 subfamilies, as well as IL-33. The IL-1 family primarily plays a role in orchestrating innate immune responses, but is also involved in adaptive immunity. Increased interest in the IL-1 family occurred following the discovery that dysregulation of IL-1 signalling underlies the pathogenesis of several monogenic autoinflammatory diseases, characterized by sterile inflammation involving the skin and other organs. This also provided increased understanding of the role of innate immunity and the IL-1 family in polygenic autoinflammatory skin conditions, such as neutrophilic dermatoses, as well as in some of the most common chronic inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa. Several therapeutic agents have been developed to inhibit the IL-1 family members and their signalling pathways. These have shown therapeutic efficacy in several chronic inflammatory skin disorders. The aim of this review is to thoroughly describe the consequences of pathological dysregulation of the IL-1, IL-33, IL-36 and IL-18 pathways in dermatological conditions and to provide a forward-looking update on therapeutic strategies targeting signalling by IL-1 family cytokines.
Cytokines of the Interleukin-1 Family
The interleukin (IL)-1 family comprises a large group of cytokines, partially sharing a conformational structure, a common receptor-binding mode, and a similar signalling pathway. All members, albeit to different degrees, are key molecules involved in a myriad of immunological responses, primarily orchestrating innate immunity and bridging innate and adaptive immune responses. The IL-1 family encompasses 11 cytokines, seven with agonistic effects on their receptors and four with antagonistic effects (Table 1).[2,3] IL-1α, IL-1β, IL-36α, IL-36β, IL-36γ, IL-33 and IL-18 bind to a cognate membrane receptor to form a binary complex, and thereupon a coreceptor is recruited so as to form a signal-competent ternary complex (Figure 1).
Most interleukin (IL)-1 family cytokines bind the cognate membrane receptor to form a so-called binary complex. Thereupon, the coreceptor, necessary for proinflammatory signal transmission, is recruited (ternary complex).
IL-1α and IL-1β[2,4] bind to a common transmembrane receptor IL-1R1, with subsequent recruitment of the coreceptor IL-1 receptor accessory protein (IL-1RAP, also named IL-1R3). Conversely, the antagonistic cytokine IL-1 receptor antagonist (IL-1Ra) engages the binding site of IL-R1 without recruiting the coreceptor IL-1R3, thus blocking signal transmission.
The IL-36 subfamily comprises IL-36α, IL-36β, IL-36γ, IL-36Ra and IL-38, with the latter two exerting an antagonistic function. The IL-36 receptor (IL-36R, IL-1R6) is the common receptor of all five members, which upon binding of IL-36α/β/γ recruits the coreceptor IL-1R3, forming a ternary complex.
IL-33 binds to its receptor IL-33R (ST2 or IL-1R4) with subsequent recruitment of IL-1R3.[3,7] Finally, IL-18 and IL-37 belong to the IL-18 subfamily and exert pro- and anti-inflammatory effects, respectively. IL-18 binds to the receptor IL-18Rα (IL-1R5, IL-1Rrp1), recognized by the coreceptor IL-18Rβ (IL-1R7), thus also forming a ternary complex.[9,10]
Receptors of the Interleukin-1 Family
The IL-1 receptor family includes 10 members, numbered from IL-1R1 to IL-1R10 (Table 2). IL-1R1 (IL-1RI, CD121a), IL-1R4 (ST2, IL-33Rα) and IL-1R6 (IL-36R, IL-1Rrp2) are the ligand-binding chains for IL-1, IL-33 and IL-36, respectively. They all use IL-1R3 as an accessory protein to form the ternary complex and induce intracellular signalling. In contrast, the ternary receptor complex of IL-18 consists of the main receptor IL-18Rα and the accessory protein IL-18Rβ. Soluble forms of IL-1 family receptors also exist, mostly acting as negative regulators (Table 3).
Interleukin-1 Receptor Accessory Protein
First described in 1995, IL-1R3 is an accessory receptor of the IL-1 family. It is not directly involved in ligand binding, although it is crucial for the constitution of the three high-affinity ternary complexes necessary for IL-1, IL-33 and IL-36 signal transmission. IL-1R3 interacts with a composite surface created by IL-1R bound to the ligand, allowing the formation of a ternary complex and the initiation of an intracellular signalling pathway. Subsequent activation of several kinases, especially nuclear factor-κB and mitogen-activated protein kinase, promotes the transmission of a strong proinflammatory signal to the cell nucleus.
Recent research has demonstrated a major role of IL-1 family cytokines in certain chronic inflammatory skin diseases (Figure 2), and the potential of blocking one or more of the family members is being explored in depth (Figure 3).[16,17] The aim of this review is to thoroughly describe the consequences of pathological dysregulation of IL-1 family signalling in chronic inflammatory skin disorders and to provide an update on the therapeutic strategies targeting these pathways.
The main dermatological diseases with solid evidence of involvement of interleukin (IL)-1, IL-36, IL-33 and IL-18 in their pathogenesis. SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis; TNF, tumour necrosis factor.
Schematic representation of seven members of the interleukin (IL)-1 family (IL-1α, IL-1β, IL-33, IL-36α, IL-36β, IL-36γ and IL-18) acting on their receptor complex with transmission of a proinflammatory signal to the nucleus. Multiple inhibitors of the inflammatory cascade at different levels are also shown. IRAK, interleukin-1 receptor-associated kinase; MAB-hR3, monoclonal antibody targeting IL-1R3; MAPK, mitogen-activated protein kinase; NF, nuclear factor; TIR, Toll–interleukin-1 receptor; TRAF, tumour necrosis factor receptor-associated factor.
The British Journal of Dermatology. 2022;186(9):925-941. © 2022 Blackwell Publishing