Taurodeoxycholate, a GPCR19 agonist, ameliorates atopic dermatitis in Balb/c mice

• Published in: European journal of immunology 2023-05, Vol.53 (5), p.e2250048-n/a
• Main Authors: Ghaderpour, Aziz, Jeong, Ju‐Young, Kim, Youn‐Hee, Zou, Yunyun, Park, Kyung‐Sun, Hong, Eun‐Ji, Koh, Young‐Jae, Seong, Seung‐Yong
• Format: Article
• Language: English
• Subjects: 1-Chloro-2,4-dinitrobenzene; Adenylate cyclase; Agonists; Animals; Atopic dermatitis; Calcium mobilization; Cytokines - metabolism; Dermatitis; Dermatitis, Atopic - drug therapy; Eczema; gpcr19; Helper cells; Inflammasomes; Inflammasomes - metabolism; Inflammation; Keratinocytes; Keratinocytes - metabolism; Lymphocytes T; Mice; Mice, Inbred BALB C; Myeloid cells; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; nlrp3; Oligomerization; Oxazolone; p2 × 7r; Pathogenesis; Taurodeoxycholate
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202250048

Keratinocytes are pivotal cells in the pathogenesis of atopic dermatitis (AD) as much as Th2 cells. In this sense, regulation of pro‐inflammatory features of keratinocytes might be useful for AD patients. P2X7R‐mediated activation of NLRP3 inflammasome (N3I) in keratinocytes and myeloid cells plays crucial roles in AD. Nonetheless, inhibition of P2X7R has not been feasible because of polymorphisms and ubiquitous expression of P2X7R. Here, we report that GPCR19 colocalizes with P2X7R, and a GPCR19 agonist (taurodeoxycholate [TDCA]) inhibits the activation of P2X7R. Noncistronically, TDCA inhibits NF‐kB activation via the adenylate cyclase‐PKA pathway and BzATP‐mediated Ca++ mobilization. Cistronically, TDCA suppresses the expression of P2X7R and N3I components in keratinocytes. NLRP3 oligomerization and the production of mature IL‐1β and IL‐18 was suppressed by TDCA treatment in keratinocytes. Topical TDCA treatment ameliorates proinflammatory features of AD in mice induced by DNCB, MC903, or oxazolone. Taken together, a GPCR19 agonist such as TDCA might inhibit P2X7R‐mediated N3I activation of keratinocytes, which is crucial for the pathogenesis of AD. TDCA is a GPCR19 agonist that effectively reduces atopic inflammation by regulating both priming phase and activation phase of the inflammasome pathway. TDCA activates GPCR19‐adenylate cyclase‐PKA pathway that inhibits NF‐kB activation, which is crucial for transcription of proinflammatory mediators (priming phase). In addition, TDCA also inhibits P2X7R‐NLRP3‐Caspase‐1 pathway necessary for maturation of IL‐1β and IL‐18 (activation phase).