IL‑37/IL‑1R8 blocks keratinocyte acantholysis via suppressing ADAM17/EGFR

Pemphigus vulgaris (PV) is a life‑threatening autoimmune blistering disease characterized by acantholysis (the loss of cell‑cell adhesion of keratinocytes) and the formation of non‑healing suprabasal intraepidermal blisters. The progression of keratinocyte acantholysis in PV is complex. Interleukin‑37 (IL‑37), which functions through receptor binding, exerts a protective role in PV. However, the specific receptor mediating the effect of IL‑37 in PV and the underlying mechanisms remain unclear. The present study found elevated levels of IL‑37, a natural suppressor of innate inflammatory and immune responses, in patients with PV. IL‑37 treatment directly suppressed both acantholysis and apoptosis in keratinocytes. Mechanistic investigations using co‑immunoprecipitation revealed that IL‑37 binds to interleukin‑1 receptor 8 (IL‑1R8). Knockdown of IL‑1R8 (or IL‑18Rα) abolished the inhibitory effects of IL‑37 on acantholysis and apoptosis. Furthermore, the IL‑37/IL‑1R8 complex suppressed epidermal growth factor receptor (EGFR) signaling, and reduced the expression of TNF‑alpha‑converting enzyme (ADAM17). Activation of EGFR using specific agonists reversed the IL‑37‑mediated reduction in acantholysis and apoptosis in HaCaT cells. In conclusion, IL‑37 treatment markedly attenuated keratinocyte dissociation and apoptosis in PV through the IL‑1R8/ADAM17/EGFR pathway. These findings provide novel mechanistic insights into the immunoregulatory functions of IL‑37.