Mast cells Initiate Type 2 Inflammation via Tryptase Released by MRGPRX2/MrgprB2 Activation in Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by T-helper 2 (Th2) inflammation as the core pathogenic mechanism. MRGPRX2 plays a key role in non-histamine allergies and neuroimmune mechanisms in chronic inflammatory dermatitis. However, the role of MRGPRX2 in AD and the development of type 2 inflammation is not yet clear. This study aimed to define the role of MRGPRX2 in type 2 inflammation development and cytokine release in AD, by determining its levels in patients with AD and healthy controls. Furthermore, MrgprB2 conditional knockout (MrgprB2^-/-) and wildtype (WT) mice were used to construct an MC903 induced AD mouse model to observe skin inflammation and cytokine release. Tryptase and its antagonist were applied separately to MrgprB2^-/- AD and WT AD mice to confirm the role of the MrgprB2-tryptase axis in the development of type 2 inflammation in AD. We found that AD severity and type 2 cytokine levels were not associated with IgE levels but were associated with MRGPRX2/MrgprB2 expression. MrgprB2^-/- AD mice showed milder phenotypes and inflammatory infiltration in the skin than WT AD mice. Tryptase released by MRGPRX2/MrgprB2 activation is involved in the release of type 2 cytokines, which contribute to the inflammatory development in AD.