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

Background: Patients with systemic lupus erythematosus (SLE) experience photosensitivity, with exposure to ultraviolet light B (UVB) driving lupus flares and triggering symptoms like joint pain, fatigue, and cutaneous lesions. Although the mechanism(s) linking UVB exposure to systemic effects are unclear, type I interferons (IFNs) are known to play a role. Our previous work has shown that TRIM21, an autoantigen in SLE, functions as a negative regulator on the pathways driving IFN expression. Here we explore how TRIM21 functions to regulate both local and systemic inflammation following UVB exposure, and how altered expression may drive cutaneous inflammation and photosensitivity in SLE.

Methods: WT (C57BL/6) and Trim21 mice were irradiated with UVB (100 mJ/cm) on shaved dorsal region of the mice on consecutive days for 1 and 3 weeks, and UVB-induced local cutaneous manifestations and systemic inflammation in blood, spleen and kidney were examined by messenger RNA expression of inflammatory and type I IFN response genes, histology, and flow cytometry. To determine the molecular targets of TRIM21 downstream of UVB, mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse dermal fibroblasts (MDF) from WT and Trim21 mice, and TRIM21 THP-1 cells.

Results: Infiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice. Most notably after UVB exposure, we observed splenomegaly and enhanced expression of IFN-stimulated genes (ISG) in the blood and spleen of Trim21 mice. Subsequent analysis showed higher expression of Siglec1, an IFN-inducible protein, on Ly6C inflammatory monocytes in the spleen and blood cells of UVB-exposed Trim21 mice, indicating a systemic IFN response. Inflammatory chemokines CXCL10 and CXCL12, both important in UVB-induced skin inflammation, were also detected at significantly higher levels in serum of Trim21 mice after UVB exposure. In addition, Trim21 mice exposed to UVB also demonstrated enhanced total IgG levels in serum accompanied by increased skin and kidney deposition of IgG and increased glomerular cellularity and size. Altogether, loss of Trim21 in mice results in enhanced systemic IFN-driven responses and mimics increased systemic disease in SLE patients following UVB exposure. To determine mechanism, we assessed UVB- and cGAMP-dependent Ifnb1 expression in Trim21 BMDMs and MDFs, noting increased responses compared to WT cells. This effect was lost in BMBMs from Trim21/Sting1 double knockout mice and skin explants, in keeping with the ability of TRIM21 to regulate cytoplasmic DNA sensing. In keeping with previous reports, we found both degradation of DDX41 and STING levels were affected in stimulated Trim21 BMDMs. Taken together, our results indicate that TRIM21 protects against IFN induction at both local and systemic levels due to a failure to restrict STING signaling.