LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes

Abstract

Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. LIM-domain only protein 4 (LMO4) is a transcription factor coregulator that promotes the assembly of multiprotein complexes to regulate mammary epithelium and keratinocyte differentiation and proliferation during embryogenesis. In this study, LMO4 has been found to be abundantly expressed in psoriatic epidermis. LMO4 expression is increased in human keratinocytes induced to differentiate by calcium ex vivo, and LMO4 overexpression induces spontaneous differentiation and growth acceleration of human keratinocytes in the absence of calcium. IL-23, a cytokine highly expressed in psoriatic skin lesions, induces differentiation and promotes proliferation of human keratinocytes. The IL-23-mediated effects are accompanied by an increase in LMO4 expression mediated by signal transducer and activator of transcription 3 through an IL-23/acutely transforming retrovirus AKT8 in rodent T-cell lymphoma/signal transducer and activator of transcription 3 pathway in keratinocytes. Knockdown of LMO4 effectively inhibits differentiation and growth of keratinocytes both ex vivo and in IL-23-injected ears of mice. LMO4 appears to mediate IL-23-related responses in psoriatic keratinocytes and is a potential therapeutic target in psoriasis.

Interleukin-17A and Keratinocytes in Psoriasis

“…Murine keratinocytes also produce biologically active IL-23 [130]. IL-23 can promote keratinocyte growth and histological acanthosis via the JAK2/AKT/STAT3/LMO4 signaling pathway [131]. LIM-domain only protein 4 (LMO4) is a LIM-domain protein that regulates keratinocyte proliferation and differentiation during embryogenesis [131].…”

“…IL-23 can promote keratinocyte growth and histological acanthosis via the JAK2/AKT/STAT3/LMO4 signaling pathway [131]. LIM-domain only protein 4 (LMO4) is a LIM-domain protein that regulates keratinocyte proliferation and differentiation during embryogenesis [131]. In addition, TNF-α is an active stimulator of IL-23 production from keratinocytes in mice and possibly in humans [131].…”

“…LIM-domain only protein 4 (LMO4) is a LIM-domain protein that regulates keratinocyte proliferation and differentiation during embryogenesis [131]. In addition, TNF-α is an active stimulator of IL-23 production from keratinocytes in mice and possibly in humans [131]. In parallel, the anti-IL-23p40 antibody (Ustekinumab) [132,133] and anti-IL-23p19 antibodies (guselkumab, risankizumab, and tildrakizumab) [133][134][135] exhibit a high efficacy to psoriasis with a superiority of risankizumab over ustekinumab [133], and guselkumab over the anti-TNF-α antibody adalimumab [134].…”

Effect of RNA Interference Targeting STAT3 Gene Combined with Ultrasonic Irradiation and SonoVue Microbubbles on Proliferation and Apoptosis in Keratinocytes of Psoriatic Lesions

“…Some reports suggest that the psoriatic epidermis shows an altered calcium metabolism, there exist specific defect of calcium influx and reduced [Ca 2+ ] i in psoriatic KCs, calcium can significantly inhibit the proliferation of KCs, and high calcium can result in a reduced proliferation of psoriatic KCs. [ 21 22 ] Our results indicated that STAT3 siRNA induced the elevation of [Ca 2+ ] i of psoriatic KCs significantly. The siRNA carried by Lipofectamine 3000 combined with ultrasonic irradiation and SonoVue microbubbles showed higher calcium fluorescence intensity mean which indicated [Ca 2+ ] i compared with that only carried by Lipofectamine 3000.…”

Resident memory T cells in tumor-distant tissues fortify against metastasis formation

“…We projected the transcriptomic transition of individual T cell subsets approaching and leaving this branching onto a heatmap, which allowed us to discover signature gene features that make up this branching point ( Figure 4E ). A cluster of 13 genes were identified; 11 of 13 of these genes were signature genes identified in the T helper 17 cell (Th17) lineage, including the effector molecule Il17f and the master transcription factor Rorc ( Chang and Dong, 2009 ; Ciofani et al, 2012 ; Gobert et al, 2018 ; Hu et al, 2013 ; Kim and Lee, 2015 ; Li et al, 2009 ; Skepner et al, 2014 ; Su et al, 2016 ; Tu et al, 2018 ; Zhou et al, 2016 ). These Tc17-like cells may serve as intermediate progenitors to separate T RM s located in the tumor or distant mammary gland mucosa.…”