Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Shirsath, N.
Molecular mechanisms of photo(chemo)therapy and mTOR inhibition in two mouse models of psoriasis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] 5; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Strobl Herbert
- Wolf Peter
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- Abstract:
- The pathophysiology of psoriasis is associated with epidermal thickening, hyperproliferative keratinocytes along with aberrant induction of IL-23/Th17 axis. This uncontrolled cellular proliferation of keratinocytes has been recently identified to be modulated by mammalian target of rapamycin (mTOR), which has emerged as a major effector molecule for proliferation and differentiation defects. mTOR may also play a role in the anti-psoriatic effects in photo(chemo)therapy, a standard treatment of psoriasis. However, the mechanisms involved in the therapeutic effects of photo(chemo)therapy and the role of mTOR signaling in functional regulating the pathogenesis of psoriasis are not yet fully understood. In the first part of the thesis, the factors responsible for the photo(chemo)therapeutic effects of psoralen+UVA (PUVA) photochemotherapy and UVB irradiation were investigated, using the imiquimod (IMQ) psoriasis mouse model. Mouse skin was treated with repetitive sub-phototoxic doses of PUVA or UVB before or during topical IMQ administration. Here, PUVA to a greater degree than UVB not only suppressed the IMQ-induced psoriatic phenotype but also pretreatment (before IMQ administration) with PUVA did to a greater degree than UVB suppress the susceptibility of murine skin to respond to IMQ. Microarray analysis showed enrichment of senescence pathway-related genes after PUVA pretreatment. PUVA downregulated baseline levels (before IMQ treatment) of IFN-gamma, IL-17 and IL-9, cytokines that drive psoriatic inflammation. However, the anti-psoriatic effect of PUVA was lost when the interval between last PUVA exposure and first IMQ administration was extended from 3 to 7 days. These findings highlight that PUVA primes the skin in such a manner as to shift the balance in favour of a reduced responsiveness to IMQ. In the second part of the thesis, the pathogenic role of mTOR signalling and its regulatory functions in psoriasis pathology were investigated. Being a conserved serine-threonine kinase, mTOR acts primarily via the regulation of protein synthesis. This was confirmed in this part of the study where mTOR signaling hyperactivation in the psoriatic skin of K5.hTGFß1 transgenic mice was normalized after PUVA therapy. Furthermore, by using an mTOR agonist in mice, it was proved that specific activation of mTOR leads to abnormal epidermal organization with disturbed involucrin distribution which is a marker of terminal differentiation. These findings not only identify mTOR pathway as an important signal integrator pivotal in the psoriatic pathomechanisms but also advocated it as a promising anti-psoriatic target. This was tested by using its antagonist rapamycin, topically applied in the IMQ model of psoriasis. Locally applied rapamycin could not only inhibit the mTOR signaling in the skin but also diminish the epidermal barrier and differentiation defect of psoriatic skin. Together, these results help better understanding the therapeutic mechanisms of photo(chemo)therapy and illuminate the role of mTOR signaling in the pathophysiology of psoriasis and its response to treatment.