TNF-α promotes CXCL-1/8 production in keratinocytes by downregulating galectin-3 through NF-κB and hsa-miR-27a-3p pathway to contribute psoriasis development

• Published in: Immunopharmacology and immunotoxicology 2023-12, Vol.ahead-of-print (ahead-of-print), p.1-9
• Main Authors: Qiu, Xiao-nan, Hong, Dan, Shi, Zhen-rui, Lu, Si-yao, Lai, Yu-xian, Ren, Yan-ling, Liu, Xiu-ting, Guo, Chi-peng, Tan, Guo-zhen, Wang, Liang-chun
• Format: Article
• Language: English
• Subjects: Animals; Chemokine CXCL1 - metabolism; CXCL-1/8; Female; Galectin 3 - genetics; galectin-3; HaCaT Cells; Humans; Interleukin-8 - metabolism; keratinocytes; Keratinocytes - metabolism; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; NF-kappa B - metabolism; Psoriasis; Psoriasis - genetics; Psoriasis - pathology; Signal Transduction; TNF-α; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0892-3973; 1532-2513
• DOI: 10.1080/08923973.2023.2229510

Treatment with TNF-α inhibitors improve psoriasis with minimize/minor neutrophils infiltration and CXCL-1/8 expression in psoriatic lesions. However, the fine mechanism of TNF-α initiating psoriatic inflammation by tuning keratinocytes is unclear. Our previous research identified the deficiency of intracellular galectin-3 was sufficient to promote psoriasis inflammation characterized by neutrophil accumulation. This study aims to investigate whether TNF-α participated in psoriasis development through dysregulating galectin-3 expression. mRNA levels were assessed through quantitative real-time PCR. Flow cytometry was used to detect cell cycle/apoptosis. Western blot was used to evaluate the activation of the NF-κB signaling pathway. HE staining and immunochemistry were used to detect epidermal thickness and MPO expression, respectively. Specific small interfering RNA (siRNA) was used to knock down hsa-miR-27a-3p while plasmids transfection was used to overexpress galectin-3. Further, the multiMiR R package was utilized to predict microRNA-target interaction. We found that TNF-α stimulation altered cell proliferation and differentiation and promoted the production of psoriasis-related inflammatory mediators along with the inhibition of galectin-3 expression in keratinocytes. Supplement of galectin-3 could counteract the rise of CXCL-1/8 but not the other phenotypes of keratinocytes induced by TNF-α. Mechanistically, inhibition of the NF-κB signaling pathway could counteract the decrease of galectin-3 and the increase of hsa-miR-27a-3p expression whereas silence of hsa-miR-27a-3p could counteract the decrease of galectin-3 expression induced by TNF-α treatment in keratinocytes. Intradermal injection of murine anti-CXCL-2 antibody greatly alleviated imiquimod-induced psoriasis-like dermatitis. TNF-α initiates psoriatic inflammation by increasing CXCL-1/8 in keratinocytes mediated by the axis of NF-κB-hsa-miR-27a-3p-galectin-3 pathway.