The IL-22 receptor, also known as IL-22 R alpha 1 and CRF2-9, is an approximately 65 kDa type I transmembrane glycoprotein that belongs to the type II cytokine receptor family (CRF). IL-22 R alpha 1 contains a 211 amino acid (aa) extracellular domain (ECD) with two fibronectin type III repeats, and a 330 aa cytoplasmic domain (1). Within the ECD, mouse IL-22 R alpha 1 shares 78%, 78%, and 94% aa sequence identity with canine, human, and rat IL-22 R alpha 1, respectively. It shares 20%‑26% aa sequence identity with the ECDs of other class II receptors IL-10 R, IL-20 R, and IL-28 R. IL-22 R alpha 1 associates with either IL-10 R beta or IL-20 R beta to form receptor complexes with distinct ligand selectivities. IL-10 R beta is a shared subunit of the IL-10, -22, -26, -28, and -29 receptors, while IL-20 R beta is a shared subunit of the IL-19, -20, -22, and -24 receptors (2). IL-22 R alpha 1/IL-10 R beta is an IL-22 responsive receptor (3, 4), and IL-22 R alpha 1/IL-20 R beta is an IL-20 or IL-24 responsive receptor (5, 6). In both cases, IL‑22 R alpha 1 functions as the high affinity ligand binding subunit, and subsequent association with IL-10 R beta or IL-20 R beta serves to stabilize the complex (3, 6‑9). IL‑22 R alpha 1 contains cytoplasmic motifs for interactions with signal transduction molecules, but association with IL-10 R beta or IL-20 R beta is required for signal transduction (3, 7). IL-22BP functions as a competitive antagonist by binding IL-22 and preventing its association with IL-22 R alpha 1 (8, 10). Even though it is a receptor for interleukins, IL‑22 R alpha 1 is not expressed on hematopoietic cells (7, 11, 12). Instead, IL-22 R alpha 1 expression is restricted to epithelial and stromal cells (7, 11‑14). IL‑22 R alpha 1 signaling promotes innate immune responses and wound healing at sites of infection and inflammation. This includes upregulation of antimicrobial, acute phase, proinflammatory, and extracellular matrix proteins as well as proteases (4, 12, 14, 15). IL‑22 R alpha 1 signaling also promotes downregulation of proteins involved in keratinocyte differentiation (4, 15).