The Molecular Basis of IL-1 Family Signaling: Strategies to Modulate Inflammation

Abstract

Interleukin-1 (IL-1) family cytokines are potent signaling molecules that influence both innate and adaptive immune systems. The IL-1 family, composed of 11 cytokines and 10 receptors, mediate inflammation to a wide array of stimuli and act on myriad cell types for diverse immunological outcomes. Altogether, IL-1 family signaling is integral to a multitude of inflammatory responses and occurs in distinct steps. First, an agonist cytokine binds its cognate receptor at high affinity. Next, this cytokine-receptor complex recruits an often-shared co-receptor. As this cytokine/receptor/co-receptor complex forms, Toll/IL-1 Receptor (TIR) domains, residing cytoplasmically, oligomerize, initiating a potent signaling cascade that results in prototypical NF-κB signal transduction. Due to the strong nature of IL-1 family signaling, multiple physiological mechanisms exist to stem this inflammatory signal, including antagonist cytokines and decoy receptors. Within the IL-1 family, the cytokines and receptors can be further divided into four subfamilies dependent on their secondary receptors. The IL-1 subfamily contains IL-1, IL-33, and IL-36 as they all share IL-1RAcP as their secondary receptor; the IL-18 subfamily is distinct as it utilizes IL-18Rβ as its secondary receptor. Here, we describe how structural biology has guided our understanding of IL-1 family signaling and how that knowledge can be leveraged for the design of therapeutics to stem aberrant cytokine signaling. In our first study, we demonstrate the feasibility of targeting a shared co-receptor, IL-1RAcP, for selective cytokine inhibition. Indeed, dependent on the specific epitope targeted on IL-1RAcP, differential cytokine signaling inhibition can be achieved. In addition, we developed our own IL-33 therapeutics by leveraging the high affinity IL-33 has for its primary receptor, the stability imparted by the secondary receptor, and the extended half-life gained through an Fc-fused receptor. Two of these molecules inhibit IL-33 signaling better than the natural antagonist sST2. Altogether, structural biology has informed our understanding of IL-1 family signaling, generated approaches to improve existing therapeutics, namely antibody epitope targeting, and led to the creation of additional IL-33 target therapeutics in the form of our “cytokine traps.”