Background/Purpose:

Photosensitivity is a common symptom in patients with systemic lupus erythematosus (SLE) and lupus skin lesions show local Type 1 Interferon (IFN-I) profiles similar to that seen in the blood. The pathogenic effect of ultraviolet light (UV) in SLE stands in contrast to the immunosuppressive effects of UV in the normal host, and UV light is used to treat various skin diseases such as psoriasis. Differences in the mechanisms linking UV light to immune suppression versus inflammation and cutaneous flares of lupus are not well understood. Here, we asked whether, and under what conditions, repetitive UVB-exposure induces IFN-I and examined what its biological effects were in the skin in the normal host.

Methods:

Shaved C57BL/6 (B6) and IFNAR KO (B6 background) mice were irradiated with narrowband UVB at 100 mJ/cm²/day for 5 consecutive days. To inhibit idoleamine 2,3-dioxygenase 1 (IDO1) in vivo,1-Methyl-d-tryptophan (1-MT) was added to drinking water (2 mg/mL) and fed to mice ad libitumbeginning 3 days prior to irradiation until experiment end. Serial punch biopsies (6 mm) were obtained at 3, 24, and 72 hrs following UVB exposure. Skin immune cell populations were analyzed by flow cytometry using CD45, CD11b, Ly6C, Ly6G, MHC II, CD64, and CD3. Skin samples were examined for mRNA expression by QPCR of pro-inflammatory cytokines and Interferon Stimulated Genes (ISG), and skin samples were analyzed histologically by H&E and for IDO1 expression by immunofluorescence

Results:

Repeated UVB exposure in normal wild-type B6 mice induced a modest IFN-I skin response with bimodal peaks at 3 and 72 hrs when compared to mice receiving a single UVB dose and non-irradiated control mice. Surprisingly, UVB-irradiated IFNAR KO mice that were unable to respond to IFN-I, had increased levels of pro-inflammatory cytokines such as TNF and IL-6 at 3 and 24 hr time points and had increased levels of inflammation by pathology scores. These findings suggest a protective role for IFN-I. Since IDO1 is an ISG and a potent suppressor of inflammation, we examined IDO1 expression following UVB. Significantly, UVB induced expression of IDO1 in the skin in B6 but not IFNAR KO mice. Consistent with this finding, inhibition of IDO1 by 1-MT treatment in B6 mice caused increased cellular infiltration, worsened histologic appearance, and increased pro-inflammatory cytokines similar to that seen in IFNAR KO mice. Infiltrating dendritic cells in IDO1-inhibited mice had decreased IL-10 levels compared to B6 mice. IDO1 inhibition in IFNAR KO mice did not alter UVB-induced inflammation consistent with IFN-I and IDO1 being in the same pathway.

Conclusion:

In the normal host, repeated doses of UVB induces an IFN-I response in the skin that attenuates pro-inflammatory signals and limits cellular recruitment. Immunosuppression is at least in part mediated though expression and activity of IDO1. This establishes a unique role for IFN-induced IDO1 in promoting the protective effects of UVB in healthy individuals. Loss of this pathway may contribute to the enhanced UVB response as observed in lupus photosensitivity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-1-interferon-in-the-skin-stimulated-by-ultraviolet-b-light-generates-immune-suppression-mediated-by-idoleamine-23-dioxygenase-1/