Metabolic rewiring in keratinocytes by miR‐31‐5p identifies therapeutic intervention for psoriasis

Wang, Maojie; Huang, Huanjie; Xu, Yong-Yue; Vos, Harmjan R.; Gulersonmez, Can; Stigter, E.C.A.; Gerritsen, Johan; Pagès-Gallego, Marc; Es, Robert van; Li, Li; Deng, Hao; Han, Lin; Huang, Run‐Yue; Lu, Chuanjian; Burgering, Boudewijn M.T.

doi:10.15252/emmm.202215674

Cited by 8 publications

(14 citation statements)

References 38 publications

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“…Importantly, blocking aspartate transporters SLC1A3 or metabolic enzyme GOT1 led to reductions of these metabolites and inhibited ATP production. Furthermore, we found significant alterations in the serum amino acid profile of psoriasis patients, resembling the profile secreted by miR-31 overexpressed keratinocytes, characterized by decreased glutamine and increased levels of aspartate, arginine, glutamate, and serine, among others (Wang et al, 2023). Intriguingly, transcriptome analysis demonstrated that CD4+ naïve T cells isolated from the peripheral blood of psoriasis patients exhibit enhanced aspartate metabolism and increased capacity for mitochondrial translation.…”

Section: Introductionmentioning

confidence: 66%

“…A growing body of evidence suggests that metabolic reprogramming plays a crucial role in shaping T cell phenotypes and functions Xu et al, 2021). Previously, we demonstrated that the overexpression of microRNA-31-5p in the keratinocytes of psoriatic lesional skin triggers the reprogramming of cell metabolism, leading to the secretion of aspartate (Wang et al, 2023). Aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGF-β, which can be reduced by inhibition of aspartate uptake and metabolism (Wang et al, 2023;.…”

Section: Introductionmentioning

confidence: 85%

“…Our previous study provided compelling evidence for the role of aspartate metabolism in enhancing Th17 cell differentiation mediated by IL-6 and TGFβ (Wang et al, 2023). However, the precise underlying mechanism remained elusive.…”

Section: Mitochondrial Respiration and Protein Translation Properties...mentioning

confidence: 99%

“…Previously, we demonstrated that the overexpression of microRNA-31-5p in the keratinocytes of psoriatic lesional skin triggers the reprogramming of cell metabolism, leading to the secretion of aspartate (Wang et al, 2023). Aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGF-β, which can be reduced by inhibition of aspartate uptake and metabolism (Wang et al, 2023;. Moreover, treatments of aspartate transporter solute carrier family 1 member 3 (SLC1A3) and glutamic-oxaloacetic transaminase 1 (GOT1) inhibitors attenuated psoriasis-like lesion damage and decreased splenic Th17 cells and serum IL-17A levels induced by imiquimod (Wang et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGF-β, which can be reduced by inhibition of aspartate uptake and metabolism (Wang et al, 2023;. Moreover, treatments of aspartate transporter solute carrier family 1 member 3 (SLC1A3) and glutamic-oxaloacetic transaminase 1 (GOT1) inhibitors attenuated psoriasis-like lesion damage and decreased splenic Th17 cells and serum IL-17A levels induced by imiquimod (Wang et al, 2023). These findings emphasize the importance of aspartate-mediated metabolic crosstalk between keratinocytes and T cells in driving the progression of psoriasis pathology.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

Wang

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Psoriasis is a complex autoimmune disease characterized by dysregulated interactions between keratinocytes and immune cells. Over the past decade, various antimicrobial peptides, chemokines, and cytokines have been discovered as key mediators in the interplay between keratinocytes and immune cells. These discoveries contribute to the development and application of biologics in the treatment of psoriasis patients. The thickened skin lesions in psoriasis likely represent a resource-limited microenvironment and, how different cells manage resource allocation is a critical question. Hence, different cells need to reprogram their metabolic patterns and establish beneficial metabolic crosstalk to coexist. However, our understanding of the metabolic reprogramming of keratinocytes and their metabolic crosstalk with other cell types in psoriasis is still limited. To address these issues, in Chapters 2 and 3, we first studied the miR-31-induced metabolic reprogramming in keratinocytes, which was found to enhance glutamine metabolism and promote the secretion of immune molecules and metabolites. The composition of these secreted substances facilitate the differentiation of CD4+ naïve T cells into Th17 cells. Especially, aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGFβ, by upregulating glycolysis to sustain the malate aspartate shuttle (MAS) and increase oxidative phosphorylation of Th17 cells. Subsequent in vitro and in vivo experiments demonstrated that targeting GLS (inhibiting glutaminolysis), SLC1A3 (blocking aspartate uptake), or GOT1 (inhibiting aspartate metabolism) can reduce Th17 cell differentiation and alleviated skin inflammation in a mouse model of psoriasis. Notably, aspartate was found elevated in the serum of psoriasis patients. In addition, the psoriasis-derived CD4+ naïve T cells expressed high levels of GOT1 and MDH1 and increased the aspartate and glutamate metabolism pathway as compared to those from healthy subjects. Collectively, our in vitro and in vivo results demonstrate that highly expressed miR-31 in keratinocytes can influence the local and systemic metabolic environment and build metabolic crosstalk with immune cells to amplify the inflammatory feedback loop in psoriasis. In Chapter 4, we demonstrate that the metabolites in the serum of psoriasis patients mediate crosstalk between different types of immune cells upon treatment with Methotrexate. These findings highlight the pervasive presence of metabolic crosstalk and its significant contribution to the therapeutic effects of methotrexate in treating psoriasis. In Chapter 5, we show that PSORI-CM02, a Chinese herbal formula that is used clinically in the treatment of psoriasis, effectively reduced HK2 expression and attenuated glycolysis in keratinocytes through the mTOR pathway. In conclusion, we uncovered the metabolic reprogramming of psoriasis keratinocytes and their metabolic crosstalk with CD4+ naïve T cells. We also provided initial insights into the therapeutic potential of targeting either the glutamine-dependent differentiated keratinocytes or the glucose-dependent proliferating keratinocytes, as well as blocking the aspartate-dependent metabolic crosstalk between keratinocytes and CD4+ naïve T cells. These studies have expanded our understanding of the interaction mechanisms between keratinocytes and immune cells, introducing metabolites such as aspartate as novel mediators and offering new strategies for the treatment of psoriasis.

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Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 85%

Section: Mitochondrial Respiration and Protein Translation Properties...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

Wang

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MiR-128-3p promotes hyperproliferation of keratinocytes and psoriasis-like inflammation by targeting SIRT1/HIF-1α

You,

Wang,

Jia

2025

Arch Dermatol Res

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Small nucleolar RNA Snora73 promotes psoriasis progression by sponging miR-3074-5p and regulating PBX1 expression

Zhang,

Guo,

Zhang

et al. 2024

Funct Integr Genomics

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Chronic psoriasis is a kind of immune-mediated skin illness and the underlying molecular mechanisms of pathogenesis remain incompletely understood. Here, we used small RNA microarray assays to scan the differential expressed RNAs in psoriasis patient samples. The downstream miRNAs and its targets were predicted using bioinformatics analysis from online bases and confirmed using fluorescence in situ hybridization and dual‑luciferase report gene assay. Cell ability of proliferation and migration were detected using CCK-8 and transwell assays. The results showed that a new snoRNA Snora73 was upregulated in psoriasis patient samples. Overexpression of Snora73 significantly increased psoriasis cells viability and migration, while knockdown of Snora73 got the opposite results. Mechanistically, our results showed that Snora73 acted as a sponge for miR-3074-5p and PBX1 is a direct target of miR-3074-5p in psoriasis cells. Furthermore, miR-3074-5p suppressed psoriasis cell proliferation and migration, while PBX1 promoted cell proliferation and migration in psoriasis. Collectively, these findings reveal a crucial role of Snora73 in progression of psoriasis through miR-3074-5p/PBX1 signaling pathway and suggest a potential therapeutic strategy.

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Metabolic rewiring in keratinocytes by miR‐31‐5p identifies therapeutic intervention for psoriasis

Cited by 8 publications

References 38 publications

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

MiR-128-3p promotes hyperproliferation of keratinocytes and psoriasis-like inflammation by targeting SIRT1/HIF-1α

Small nucleolar RNA Snora73 promotes psoriasis progression by sponging miR-3074-5p and regulating PBX1 expression

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