Down-regulation of Gremlin1 inhibits inflammatory response and vascular permeability in chronic idiopathic urticaria through suppression of TGF-β signaling pathway

• The mechanism of silencing GREM1 is firstly explored in CIU. • High tryptase, β-hexosaminase, and histamine in CIU serum. • Silencing GREM1 inhibits TGF-β and inflammatory response in CIU. • Inhibited TGF-β suppresses CIU development. • GREM1 and TGF-β are the new treatment targets for CIU. Chronic idiopathic urticaria (CIU) is an unfavorable skin condition which could be maintained for six weeks or longer time. Gremlin1 (GREM1) was recently applied in treatments of many diseases. However, the possible regulatory mechanism of GREM1 in CIU remained unclear. This study aimed to explore the regulatory effects of GREM1 on the inflammatory response and vascular permeability mediated by mast cells of CIU via TGF-β signaling pathway. Initially, microarray analysis was used to identify CIU-related differentially expressed genes and the potential mechanism of this gene. A mouse model of CIU was established. To explore the functional role of GREM1 in CIU, the modeled mice were then injected with GREM1-siRNA, SRI-011381 (the activator of TGF-β signaling pathway), or both, followed by serum test, and immunoglobulin detection. The levels of inflammatory factors and tryptase, β-hexosaminase, histamine in the serum were detected. Besides, vascular endothelial cell permeability and the target relation between GREM1 and TGF-β were also examined. Mice injected with SRI-011381 exhibited higher levels of tryptase, β-hexosaminase, histamine, inflammation-related factors and increased vascular endothelial cell permeability, while GREM1-silenced mice yet expressed opposite tendency. Silencing of GREM1 was demonstrated to inhibit the TGF-β signaling pathway. Taken together, our results demonstrated that down-regulation of GREM1 could potentially impede inflammatory response and vascular permeability by suppressing TGF-β signaling pathway. GREM1 may promote the development of prognosis management and therapeutic treatment in CIU.