Adenosine A2A receptor activation regulates the M1 macrophages activation to initiate innate and adaptive immunity in psoriasis

• Published in: Clinical immunology (Orlando, Fla.) Vol. 266; p. 110309
• Main Authors: Lu, Yan, Zhu, Wu, Zhang, Guan Xiong, Chen, Jun Chen, Wang, Qiao Lin, Mao, Man Yun, Deng, Si Chun, Jin, Li Ping, Liu, Hong, Kuang, Ye Hong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2024
• Subjects: A2AR; CXCL10/11; KRT16; M1 macrophage; NF-κB; Psoriasis; Th1/17; NF-κB; Psoriasis; M1 macrophage; KRT16; CXCL10/11; A2AR; Th1/17
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2024.110309

Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis. [Display omitted] •A2AR regulated the progression of psoriasis by controlling M1 macrophage activation.•A2AR activation inhibited the expression of KRT16 in M1 via NF-κB signaling pathway.•The KRT16 expression was first found in M1, not only in keratinocytes.•KRT16 knockdown in M1 reduced the secretion of CXCL10/11 which recruting T cells in psoriasis.•The main sources of CXCL10/11 are macrophages and dendritic cells rather than keratinocytes in psoriasis.•A2aR activation inhibited Th1/17 differentiation mediated by M1 macrophage activation.