IL-1Rrp2, also known as IL-1RL2/ IL-1R6, belongs to the family of IL-1 receptor, which contains Toll/IL-1R (TIR) domain in the cytoplasmic region. IL-1Rrp2 consists of Immunoglobulin-like extracellular domain, a transmembrane region and a cytoplasmic region. Upon binding of IL-36α, IL-36β or IL-36γ, IL-1Rrp2 recruits its co-receptor, IL-1R accessory protein (IL-1RAcP) and forms a heterodimeric complex, which in turn activates the downstream pathways, including NF-κB, mitogen-activated protein kinase (MAPK), JNK, ERK, IL-8 promoter, and IL-6 secretion. The activation profile of the IL-36/ IL-1Rrp2/ IL-1RAcP complex are similar to IL-1. IL-36 family (IL-36α, β, γ) and IL-1Rrp2 are detected at higher levels in skin and airway tissues, implicating that they are involved in local inflammatory response as an epithelial barrier. IL-36Ra can bind to IL-1Rrp2 but inhibits IL-36 signaling. It has been reported that IL-38 binds to IL-1Rrp2 in vitro. Recent studies demonstrated that na?ve CD4+ T cells constitutively express IL-1Rrp2 and IL-36 cytokines enhance their proliferation and Th1 polarization in synergy with IL-12. In IL-1Rrp2 deficient mice, imiquimod-induced expansion of dermal IL-17-producing γδ T cells and psoriasiform dermatitis are released.