LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating the STAT3 pathway and downregulating KHSRP.

Psoriasis is a chronic inflammatory disease characterized by increased keratinocyte proliferation and local inflammation. Long noncoding RNAs (lncRNAs) play important regulatory roles in many immune-mediated diseases, including psoriasis. In this study, we aimed to investigate the role and mechanism of lnc-SPRR2G-2 (SPRR2G) in M5-treated psoriatic keratinocytes. Fluorescence in situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) showed that lnc-SPRR2G-2 was significantly upregulated in psoriasis tissues and psoriatic keratinocytes. In psoriatic keratinocytes, functional and molecular experiment analyses demonstrated that SPRR2G regulated proliferation, cell cycle and apoptosis, and induced the expression of S100 calcium binding protein A7 (S100A7), interleukin (IL)-1ß, IL-8 and C-X-C motif chemokine ligand 10 (CXCL10). The function of SPRR2G in psoriasis is related to the STAT3 signaling pathway and can be inhibited by a STAT3 inhibitor. Moreover, KH-type splicing regulatory protein (KHSRP) was proved to be regulated by lnc-SPRR2G-2 and to control the mRNA decay of psoriasis-related cytokines (p < 0.05). In summary, we reported the functions of lnc-SPRR2G-2 and KHSRP in psoriasis. Our findings provide new insights for the further exploration of the pathogenesis and treatment of psoriasis.

Pentraxin 3 exacerbates psoriasiform dermatitis through regulation of macrophage polarization.

OBJECTIVE: To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice. METHODS: An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3-/-) and wild-type (Ptx3+/+) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization. RESULT: The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3-/- mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3+/+ mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups. CONCLUSIONS: This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.

eIF4E plays the role of a pathogenic gene in psoriasis, and the inhibition of eIF4E phosphorylation ameliorates psoriasis-like skin damage.

Psoriasis is a complex inflammatory skin disease with uncertain pathogenesis. eIF4E (eukaryotic translation initiation factor 4E) and its phosphorylation state p-eIF4E are highly expressed in psoriatic tissues. However, the role eIF4E played in psoriasis is still unclear. To investigate the function of eIF4E and p-eIF4E in psoriasis and to figure out whether eFT-508 (Tomivosertib, eIF4E phosphorylation inhibitor) can relieve the disease severity and become a promising candidate for the psoriasis treatment. We first verified the expression of eIF4E and p-eIF4E in psoriasis patients' lesional skin. Then, we demonstrated the effect of eIF4E and p-eIF4E on the abnormal proliferation and inflammatory state of keratinocytes by using eIF4E-specific small interfering RNA (si-eIF4E) and eFT-508. In this study, all cell experiments were performed under the psoriasis-model condition. Moreover, the external application of eFT-508 on imiquimod (IMQ)-induced psoriasis mice was performed to explore its potential clinical value. Results showed that eIF4E and p-eIF4E were significantly overexpressed in skin lesions of psoriasis patients. Knocking down eIF4E or adding eFT-508 can relieve the abnormal proliferation and the excessive inflammatory state of keratinocytes by reducing the expression of cyclin D1, IL-1ß, CXCL10, IL23, Wnt 5a, NBS1 and p-AKT from mRNA or protein levels. Furthermore, these results were consistent with those obtained from the in vitro experiments. Then, we conclude that eIF4E plays the role of the pathogenic gene in psoriasis, and eFT-508 may be a promising candidate for anti-prosoriasis drugs.

LPCAT1 Facilitates Keratinocyte Hyperproliferation and Skin Inflammation in Psoriasis by Regulating GLUT3.

Psoriasis is a chronic and relapsing inflammatory skin disorder characterized by keratinocyte hyperproliferation and immune cell infiltration. LPCAT1 has been identified as a cancer promoter in cutaneous squamous cell carcinoma by us, yet its role in psoriasis remains elusive. In this study, we report that LPCAT1 is highly expressed in psoriatic skin lesions. LPCAT1 promotes keratinocyte hyperproliferation and enhances the secretion of IL-1ß, IL-6, CXCL10, CCL20, S100A9, and platelet-activating factor. In psoriasiform keratinocytes, LPCAT1 promotes proliferation and inflammatory mediator production by activating protein kinase B/NF-κB and signal transducer and activator of transcription 3 signaling pathways. Furthermore, LPCAT1 inhibition attenuated epidermal hyperplasia and relieved skin inflammation in imiquimod-treated mice. Importantly, we identify the glucose transporter GLUT3, a recently reported promising target to mitigate T helper 17 cell-mediated inflammatory diseases, as a critical downstream effector of LPCAT1. GLUT3 deficiency impaired the proliferation and inflammation of psoriatic keratinocytes. LPCAT1 regulates GLUT3 in keratinocytes through NF-κB/signal transducer and activator of transcription 3 signaling, enhancing keratinocyte glycolysis and promoting proproliferative and proinflammatory effects. In addition, suppressing GLUT3 in mice alleviated imiquimod-induced dermatitis. Taken together, our study indicates the critical role of the LPCAT1-GLUT3 axis in psoriasis pathogenesis and proposes LPCAT1 or GLUT3 as a potential therapeutic target for psoriasis.

KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the Transcription of PIK3R3.

The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 in vitro and in vivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-κB pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.

Downregulation of miRNA miR-1305 and upregulation of miRNA miR-6785-5p may be associated with psoriasis.

Background: The role of serum extracellular vesicles (EVs) is less known in psoriasis. Objectives: To explore the transcriptomic profile of serum EVs and the potential biomarkers in psoriasis. Methods: EVs were isolated by differential ultracentrifugation and identified by transmission electron microscope. The diameters of EVs were detected using nanoparticle tracking analysis. Serum EVs-keratinocyte interaction was observed through confocal fluorescence microscopy. miRNA microarray and mRNA microarray were performed in serum EVs (n = 4) and skin lesions (n = 3), respectively. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization were used to detect the expression of miRNAs in serum EVs and skin lesions (n = 15). Bioinformatics analysis was performed to predict the potential target genes and functions of miR-1305 and miR-6785-5p. Western blot, CCK-8 and enzyme-linked immunosorbent assay (ELISA) were used to detect the EVs' biomarkers, keratinocytes proliferation and cytokines secretion. Results: A total of 16 miRNAs and 1,725 mRNAs were significantly dysregulated in serum EVs and skin lesions, respectively. miR-1305 was down-regulated and miR-6785-5p was upregulated in both serum EVs and skin lesions. Serum EVs could be taken up by keratinocytes. miR-1305 was downregulated and miR-6785-5p were upregulated in keratinocytes after co-cultured with psoriasis serum EVs compared with controls. Psoriasis serum EVs promoted keratinocyte proliferation and the secretion of CCL20 and IL-8. Serum EVs miR-1305 and miR-6785-5p were associated with disease severity. Conclusion: Serum EVs might be involved in the activation of keratinocytes through loaded miRNAs in psoriasis. Serum EVs miR-1305 and miR-6785-5p may be associated with psoriasis.