M-5

Psoriasis is a common and immune-mediated skin disease related to keratinocytes hyperproliferation and inflammation. Fos-like antigen-1 (FOSL1) is an important transcription factor involved in various diseases. FOSL1 has been reported to be differentially expressed in psoriasis. However, the roles and mechanism of FOSL1 in psoriasis progression remain largely unknown. FOSL1 is an upregulated transcription factor in psoriasis and increased in M5-treated HaCaT cells. FOSL1 had a diagnostic value in psoriasis, and positively associated with PASI score, TNF-α and IL-6 levels in psoriasis patients. FOSL1 silencing attenuated M5-induced HaCaT cell hyperproliferation through decreasing cell viability and proliferative ability and increasing cell apoptosis. FOSL1 knockdown mitigated M5-induced NLRP3 inflammasome activation and it-mediated inflammatory cytokine (IL-6, IL-8 and CCL17) expression. TRAF3 expression was increased in psoriasis patients and M5-treated HaCaT cells. FOSL1 transcriptionally activating TRAF3 in HaCaT cells. TRAF3 overexpression reversed the suppressive effects of FOSL1 silencing on M5-induced hyperproliferation and NLRP3-mediated inflammation. FOSL1 knockdown attenuated M5-induced NF-κB signaling activation by reducing TRAF3. Activation of NF-κB signaling reversed the effects of FOSL1 knockdown on hyperproliferation and inflammation in M5-treated cells. FOSL1 silencing prevented M5-induced hyperproliferation and NLRP3-mediated inflammation of keratinocytes by inhibiting TRAF3-mediated NF-κB activity, indicating FOSL1 might act as a therapeutic target of psoriasis.

Psoriasis is a prevalent, long‐term skin condition characterized by inflammation. Keratinocytes (KCs) are important effector cells that release inflammatory factors and chemokines to promote the inflammatory cascade in psoriasis. However, the mechanisms underlying the activation of KCs in psoriasis remain unclear. Livin suppresses apoptotic proteins and directly affects the growth and spread of cancer cells. Livin expression reportedly increases significantly in lesions of patients with psoriasis; however, its specific role in KC activation remains unknown. This study aimed to examine the impact of Livin on KC activation and the subsequent release of inflammatory mediators.

Immunofluorescence staining, reverse transcription‐quantitative polymerase chain reaction, enzyme‐linked immunosorbent assay (ELISA), and western blotting were used to assess Livin expression in patients with psoriasis, an imiquimod (IMQ)‐induced psoriasis‐like mouse model, and M5‐treated HaCaT cells. To investigate the role of Livin in KCs, we performed RNA sequencing and proteomic analysis of Livin‐knockdown (knockdown‐HaCaT) and negative control (NC‐HaCaT) cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for enrichment analyses. Moreover, the effect of Livin expression on the release of inflammatory mediators in KCs was verified using ELISA.

Livin expression was higher in KCs of patients with psoriasis than in those healthy controls. Livin expression in HaCaT cells treated with M5 increased significantly over time. Livin expression was higher in the skin lesions of the IMQ mouse model than in the control group. Proteomic analysis and RNA sequencing used to investigate the function of Livin in HaCaT cells revealed its potential role in mediating KC activation and inflammatory mediator release, which affected the pathology of psoriasis.

Livin expression played an effect on KCs activation, which induced release of inflammatory mediators and up‐regulation of keratin. This study provides a new effector molecule for the mechanism of inflammatory response in psoriasis.