Psoriasis is an inflammatory skin disease characterized by keratinocyte proliferation and inflammatory cell infiltration induced by IL-17. However, the molecular mechanism through which IL-17 signaling in keratinocytes triggers skin inflammation remains not fully understood. Pyruvate kinase M2 (PKM2), a glycolytic enzyme, has been shown to have non-metabolic functions. Here, we report that PKM2 mediates IL-17A signaling in keratinocytes triggering skin psoriatic inflammation. We find high expression of PKM2 in the epidermis of psoriatic patients and mice undergoing psoriasis models. Specific depletion of PKM2 in keratinocytes attenuates the development of experimental psoriasis by reducing the production of pro-inflammatory mediators. Mechanistically, PKM2 forms a complex with Act1 and TRAF6 regulating NF-κB transcriptional signaling downstream of the IL-17 receptor. As IL-17 also induces PKM2 expression in keratinocytes, our findings reveal a sustained signaling circuit critical for the psoriasis-driving effects of IL-17A, suggesting that PKM2 is a potential therapeutic target for psoriasis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.celrep.2022.111897 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of hidradenitis suppurativa.
J Dermatol Sci
November 2024
Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:
Background: Mutations in gamma-secretase complex (GSC) genes are associated with hidradenitis suppurativa (HS), and toll-like receptor (TLR) 2 is elevated in HS lesions. However, it remains unclear whether TLR2 is upregulated in the skin lesions of patients with HS with GSC gene variants, and the role of its upregulation in the pathogenesis of this disease are unknown.
Objective: To investigate the role of TLR2 upregulation in NCSTN and PSENEN knockdown keratinocytes.
Updates on the Pathogenesis of Canine Atopic Dermatitis and Feline Atopic Skin Syndrome: Part 2, the Skin Barrier, the Microbiome, and Immune System Dysfunction.
Vet Clin North Am Small Anim Pract
December 2024
College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 408 Raymond Stotzer Parkway, College Station, TX 77845, USA. Electronic address:
Alterations in the lipid layer and intercellular corneocyte connections can lead to increased allergen penetration through the skin surface. A normal cutaneous microbiome keeps the opportunistic pathogen Staphylococcus pseudintermedius levels low, but allergic inflammation leads to decreased diversity and increase in S pseudintermedius. Keratinocytes sound the initial allergen alarm via cytokine signaling and promote T-helper 2 (Th-2) inflammation.
View Article and Find Full Text PDFGeneralized pustular psoriasis: immunological mechanisms, genetics, and emerging therapeutics.
Trends Immunol
December 2024
College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:
Generalized pustular psoriasis (GPP) is a rare human autoinflammatory disorder with life-threatening systemic effects. Keratinocyte-derived interleukin (IL)-36 signaling has been identified as a key mediator of immune response in the skin of affected individuals. Recognition of various mutations along the IL-36 axis and the downstream nuclear transcription factor κB (NF-κB) signaling have established GPP as genetically, immunologically, and histopathologically distinct and amenable to immunomodulation, which is epitomized by the recent success of IL-36 antagonism.
View Article and Find Full Text PDFExploring the ncRNA landscape in exosomes: Insights into wound healing mechanisms and therapeutic applications.
Int J Biol Macromol
December 2024
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP 226002, India. Electronic address:
Exosomal non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, have emerged as crucial modulators in cellular signaling, influencing wound healing processes. Stem cell-derived exosomes, which serve as vehicles for these ncRNAs, show remarkable therapeutic potential due to their ability to modulate wound healing stages, from initial inflammation to collagen formation. These ncRNAs act as molecular signals, regulating gene expression and protein synthesis necessary for cellular responses in healing.
View Article and Find Full Text PDFFermented Fish Collagen Diminished Photoaging-Related Collagen Decrease by Attenuating AGE-RAGE Binding Activity.
Curr Issues Mol Biol
December 2024
Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
Ultraviolet (UV) irradiation causes skin wrinkles and decreases elasticity. UV also increases binding between advanced glycation end products (AGEs) and the receptor for AGEs (RAGE), resulting in increased inflammation and activation of NF-κB. We evaluated whether fermented fish collagen (FC) could decrease photoaging via decreasing AGE-RAGE binding activity, which was associated with decreased TNF-α and NF-κB levels in UV-irradiated keratinocytes and animal skin.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!