Abstract:
Psoriasis is a chronic autoimmune skin disease that affects approximately 2% of the people worldwide, therefore reduces quality of life of the affected persons. In addition, it is often associated with comorbidities, such as arthritis, enhanced risk for cardiovascular diseases, diabetes or metabolic syndromes. This inflammatory disease is characterized by keratinocyte hyperproliferation and a massive infiltration of neutrophils, macrophages, and T cells, which is triggered by environmental factors like incisions in genetically predisposed individuals. The transcription factor NF-κB is assumed to be an essential mediator in the pathogenesis of psoriasis, since in lesional psoriatic skin enhanced levels of activated, phosphorylated NF-κB dimers were observed. The action of the NF-κB heterodimer itself is regulated via IκB proteins such as IκBζ and IκBNS, which are localized in the nucleus where they modulate the transcription of NF-κB-dependent target genes. Especially IκBζ is in central focus in the scientific community, since its encoding gene NFKBIZ is overexpressed in human psoriatic lesions, whereas its global genetic depletion protects against psoriasis progression in different psoriasis-like mouse models. Although IκBζ has emerged as a novel regulator for pathogenesis of psoriasis, it remains unclear whether IκBζ expression in keratinocytes or CD4+ immune cells is relevant for its pathogenic effects. Moreover, the contribution of IκBNS to psoriasis progression is unknown.
In order to address these questions, we generated keratinocyte- as well as CD4-specific IκBζ-deficient mice and performed imiquimod-triggered psoriasis mouse models. Our results demonstrate that KC-derived IκBζ drives psoriasis development and associated systemic inflammation, whereas IκBζ expressed by CD4+ cells plays a minor role in driving skin inflammation, since abrogated IL-17/TNFα signaling in CD4+ IκBζ KO alone is not sufficient to block psoriasis progression. IL-17 induces important pathogenetic factors of psoriasis such as antimicrobial peptides, epidermal hyperproliferation and neutrophil recruitment, thus blockade of this pathway is considered a therapeutic approach. To strengthen these observations, we additionally performed IL-36- and IL-23-driven models in KC-specific knockout mice. Absence of IκBζ in keratinocytes led to suppressed psoriasis-associated gene expression (especially immune cell recruitment and pro-inflammatory cytokines) and protection against typical pathogenic effects. The role of another IκB member was also investigated in this thesis, since an effect on the development of psoriasis was suspected for IκBNS as well. However, initial results demonstrated that IMQ-induced psoriasis-like skin inflammation is unaffected by global IκBNS depletion, therefore a minor contribution of this atypical inhibitor can be suggested in psoriasis disease.
Furthermore, the impact of IκBNS in dendritic cell differentiation and functionality was under explored. Our results demonstrated that IκBNS suppresses differentiation as well as functionality of dendritic cells in several in vitro models. Additionally, we were able to show initial data that MHC class II activation is blocked by IκBNS via CIITA inhibition.
Taken together, these results provide insight into the contribution of IκBζ and IκBNS in psoriasis and immune cell activation; esp. the contribution of KC-derived IκBζ in dermatitis protection, which in turn uncovers a pivotal role as key mediator of psoriasis.
Psoriasis