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        PDIA3 does not control NOTCH2 signaling in myeloid dendritic cells

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        PDIA3 does not control NOTCH2 signaling in myeloid dendritic cells - Hélène van den Heuvel 20221031.docx (8.101Mb)
        Publication date
        2024
        Author
        Heuvel, Hélène van den
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        Summary
        Non-infectious uveitis refers to a collection of intraocular inflammatory conditions with a presumed autoimmune aetiology of unknown cause. It remains one of the leading causes of blindness for which no long-term and safe treatment options are currently available. NIU disease biology remains poorly understood. Previous research has demonstrated that pro-inflammatory CD36+ CX3CR1+ cDC2s, which skew naïve T-cells towards pro-inflammatory lineages , are abundant in the eyes of NIU patients. These cDC2s are proposed to emerge in response to compromised NOTCH2 signaling . As vitamin D3 may activate the NOTCH2 pathway via PDIA3 and vitamin D levels are low in NIU patients, it is hypothesized that low vitamin D3 levels could contribute to the pro-inflammatory phenotype associated with NIU. We aimed to determine whether PDIA3 affects NOTCH2 signaling in the context of the molecular mechanisms driving NIU. Using qPCR, NOTCH2 pathway activity and PDIA3 expression by cDC2s were confirmed. THP-1 cells were employed as the primary cDC2 model. Using CRISPR Cas9 technology, PDIA3 KO THP-1 cells were generated. Evaluation of PDIA3 KO THP-1 cells revealed expression of PDIA3 was reduced but no changes were detected on protein level using flow cytometry. Other NOTCH2 pathway components remained unaffected. In conclusion, PDIA3 is expressed by cDC2s and the NOTCH2 pathway is active in these cells. The current data do not provide sufficient evidence that NOTCH2 pathway activation is governed by PDIA3 and vitamin D3. A better suited model is required to gain additional knowledge on the mechanisms driving NIU.
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        https://studenttheses.uu.nl/handle/20.500.12932/48148
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