Macrophages mediate psoriasis via Mincle-dependent mechanism in mice

• Published in: Cell death discovery 2023-04, Vol.9 (1), p.140-140, Article 140
• Main Authors: Tan, Rui-zhi, Zhong, Xia, Han, Rang-yue, Xie, Ke-huan, Jia, Jian, Yang, Ye, Cheng, Mei, Yang, Chun-yan, Lan, Hui-yao, Wang, Li
• Format: Article
• Language: English
• Subjects: 631/250/256/2515; 692/699/4033; Adoptive transfer; Apoptosis; Biochemistry; Biomedical and Life Sciences; Bisphosphonates; Cell Biology; Cell Cycle Analysis; Clodronic acid; Imiquimod; Inflammatory diseases; Life Sciences; Liposomes; Macrophages; NF-κB protein; Phenotypes; Psoriasis; PU.1 protein; Skin diseases; Skin lesions; Stem Cells; Syk protein; Topical application
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01444-8

Psoriasis is currently considered to be an immune and inflammatory disease characterized by massive immune cells infiltration including macrophages. It has been reported that macrophage-inducible C-type lectin (Mincle) is essential to maintain the pro-inflammatory phenotype of M1 macrophages, however, its role and mechanisms in psoriasis remain largely unknown. A model of psoriasis was induced in mice by a daily topical application of imiquimod for 7 days. Role and mechanisms of Mincle in macrophage-mediated psoriasis were investigated in clodronate liposomes induced macrophage depletion mice followed by adoptively transferring with Mincle-expressing or -knockout (KO) macrophages, and in macrophage specific Mincle knockout mice (Mincle loxp/loxp /Lyz2-cre +/+ ). Finally, a Mincle neutralizing antibody was employed to the psoriasis mice to reveal the therapeutic potential for psoriasis by targeting Mincle. Mincle was highly expressed by M1 macrophages in the skin lesions of patients and mice with psoriasis. Clodronate liposomes-induced macrophage depletion inhibited psoriasis in mice, which was restored by adoptive transfer with Mincle-expressing macrophages but not by Mincle-KO macrophages. This was further confirmed in macrophage-specific Mincle-KO mice. Mechanistically, macrophages mediated psoriasis via the Mincle-Syk-NF-κB pathway as blocking macrophage Mincle inhibited Syk/NF-κB-driven skin lesions and epidermal injury in vivo and in vitro. We also found that LPS induced Mincle expression by M1 macrophages via the PU.1-dependent mechanism. Most importantly, we revealed that targeting Mincle with a neutralizing antibody significantly improved psoriasis in mice. In summary, our findings demonstrated that macrophages mediate psoriasis in mice via the Mincle-dependent mechanism, targeting Mincle may represent as a novel therapy for psoriasis. A simplified pathway model of Mincle in macrophage-mediated psoriasis.