Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways

Tumurkhuu, G.; Moore, R.; Perri, G.; De Los Santos, G.; Laguna, D. E.; Gibb, D.; Carriere, J.; Stehlik, C.; Jefferies, C.

doi:10.1101/2024.04.10.588897

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bioRxiv · 10.1101/2024.04.10.588897

Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways

Tumurkhuu, G.·Moore, R.·Perri, G.·De Los Santos, G.·Laguna, D. E.·Gibb, D.·Carriere, J.·Stehlik, C.·Jefferies, C.

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Abstract

BackgroundExposure of systemic lupus erythematosus (SLE) patients to ultraviolet light B (UVB) triggers local and systemic inflammation, with cytosolic DNA sensing and induction of type I interferons (IFNs) known to play a role. We previously identified TRIM21 as a negative regulator of DNA sensing and IFN expression. Here we explore the role of TRIM21 in regulating local and systemic responses following UVB exposure. MethodsWT (C57BL/6) and Trim21-/- mice were irradiated with UVB (100mJ/cm2) daily for 1 and 3 weeks, and UVB-induced inflammation in skin, blood, and spleen were analyzed by qPCR, histology, RNA sequencing and flow cytometry. Mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) from WT and Trim21-/- mice, and TRIM21-/-THP-1 cells. ResultsInfiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice, however Trim21-/-mice developed splenomegaly, enhanced total IgG levels and IFN-stimulated genes (ISG) in the blood and spleen. Enhanced basal and UVB-dependent Ifnb1 expression was observed in Trim21-/- BMDMs and MDFs, which was dependent on the cytosolic DNA sensing cGAS-STING pathway. Mechanistically, we found both degradation of DDX41 and STING levels were impaired in stimulated Trim21-/-BMDMs. ConclusionTaken together, our results indicate that TRIM21 protects against IFN induction at local and systemic levels through restricting STING signaling. Our finding that reduced levels of TRIM21 are observed in SLE patients with cutaneous involvement indicates a potential role for TRIM21 in guarding against systemic flare in SLE patients.

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Tumurkhuu, G., Moore, R., Perri, G., De Los Santos, G., Laguna, D. E., Gibb, D., Carriere, J., Stehlik, C., Jefferies, C.. 2024-04-14. Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways. https://doi.org/10.1101/2024.04.10.588897

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