Damage-associated molecular patterns in necroptosis-dependent skin inflammation

Fernandez Nasarre, Africa 2022. Damage-associated molecular patterns in necroptosis-dependent skin inflammation. PhD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (99MB) | Preview
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (643kB)

Abstract

Necroptosis is a regulated form of cell death generally dependent on the activation of receptor interacting serine/threonine kinase 3 (RIPK3) and its substrate mixed lineage kinase domain like pseudokinase (MLKL). MLKL phosphorylation leads to its oligomerisation and translocation to the membrane, where it forms pore that result in homeostasis disruption and cell death. Membrane disruption allows the release of damage-associated molecular patterns (DAMPs) such as interleukin (IL) 33 and high mobility group box protein 1 (HMGB1) to the extracellular space, which act as potent pro-inflammatory molecules alerting the immune system. Specific deletion of Caspase 8 (Casp-8) in epidermal keratinocytes (Casp-8EKO) causes acute necroptosis-dependent psoriasis-like inflammation in the skin. However, the relative contribution of IL-33 and HMGB1 to necroptosis in the skin is poorly understood. The results reported here indicate that HMGB1 induces phosphorylation of MLKL in normal human epidermal keratinocytes (NHEKs) in vitro, which might occur independently of RIPK3. Additionally, deletion of IL-33 or its receptor, suppression of tumorigenicity 2 (ST2), leads to a major rescue of the skin inflammatory phenotype in the Cap8EKO model, identifying IL33 as an early mediator of necroptosis-dependent skin inflammation. Reduced skin inflammation is associated to a decreased IL-33-mediated recruitment of granulocytes, which might be responsible for mediating inflammation through tumour necrosis factor (TNF) production. In contrast, HMGB1/RAGE signalling does not contribute to inflammation in the necroptosis Casp-8EKO model. Together, these findings bridge an important gap between DAMPs and extend our knowledge of the molecular mechanisms involved in necroptosis-dependent skin inflammation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	8 November 2022
Last Modified:	06 Jan 2024 03:34
URI:	https://orca.cardiff.ac.uk/id/eprint/154019

Actions (repository staff only)

Edit Item