Back to Search
Start Over
Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
- Source :
- Cell Death and Disease, Vol 11, Iss 2, Pp 1-14 (2020), Cell Death & Disease
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1β, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.
- Subjects :
- Keratinocytes
Cancer Research
Programmed cell death
Indoles
Necroptosis
Immunology
Anti-Inflammatory Agents
Inflammation
Article
Cellular and Molecular Neuroscience
RIPK1
Psoriasis
Animals
HaCaT Cells
Humans
Medicine
Phosphorylation
lcsh:QH573-671
Protein Kinase Inhibitors
Skin
Acrylamides
Mice, Inbred BALB C
Sulfonamides
Imiquimod
lcsh:Cytology
business.industry
Imidazoles
Chronic inflammation
Cell Biology
medicine.disease
Disease Models, Animal
HaCaT
medicine.anatomical_structure
Receptor-Interacting Protein Serine-Threonine Kinases
Cancer research
Cytokines
Female
Inflammation Mediators
Signal transduction
medicine.symptom
business
Keratinocyte
Protein Kinases
Signal Transduction
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....e97ecdfa3725d70e416de85c18b5e725