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. 2016 Dec;25(12):969-976.
doi: 10.1111/exd.13108.

Fn14 deficiency protects lupus-prone mice from histological lupus erythematosus-like skin inflammation induced by ultraviolet light

Jessica Doerner  1 , Samantha A Chalmers  1 , Adam Friedman  2 , Chaim Putterman  1   3
Affiliations

Fn14 deficiency protects lupus-prone mice from histological lupus erythematosus-like skin inflammation induced by ultraviolet light

Jessica Doerner et al. Exp Dermatol. 2016 Dec.

Abstract

The cytokine TNF-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are involved in cell survival and cytokine production. The TWEAK/Fn14 pathway plays a role in the pathogenesis of spontaneous cutaneous lesions in the MRL/lpr lupus strain; however, the role of TWEAK/Fn14 in disease induced by ultraviolet B (UVB) irradiation has not been explored. MRL/lpr Fn14 knockout (KO) was compared to MRL/lpr Fn14 wild-type (WT) mice following exposure to UVB. We found that irradiated MRL/lpr KO mice had significantly attenuated cutaneous disease when compared to their WT counterparts. There were also fewer infiltrating immune cells (CD3+ , IBA-1+ and NGAL+ ) in the UVB-exposed skin of MRL/lpr Fn14KO mice, as compared to Fn14WT. Furthermore, we identified several macrophage-derived proinflammatory chemokines with elevated expression in MRL/lpr mice after UV exposure. Depletion of macrophages, using a CSF-1R inhibitor, was found to be protective against the development of skin lesions after UVB exposure. In combination with the phenotype of the MRL/lpr Fn14KO mice, these findings indicate a critical role for Fn14 and recruited macrophages in UVB-triggered cutaneous lupus. Our data strongly suggest that TWEAK/Fn14 signalling is important in the pathogenesis of UVB-induced cutaneous disease manifestations in the MRL/lpr model of lupus and further support this pathway as a possible target for therapeutic intervention.

Keywords: MRL-lpr/lpr; TNF-like weak inducer of apoptosis; cutaneous lupus; macrophages; photosensitivity.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1
Fn14 deficient MRL/lpr mice are less photosensitive. (a) Shown here are representative H&E images from UVB-exposed and non-exposed skin of MRL/lpr Fn14 WT and KO mice. The arrowhead represents acanthotic epidermis and the arrow points toward an epidermal pustule (left panel). Histopathological skin scores from 13–15 week old female UVB-irradiated MRL/lpr Fn14WT (n=14) and MRL/lpr Fn14KO mice (n=15) are shown in the right panel. (b) Representative images of TUNEL stained paraffin-embedded skin sections from UVB-irradiated MRL/lpr Fn14WT (n=6) and MRL/lpr Fn14KO mice (n=6) (top panel). TUNEL positive cells in the epidermis and dermis were counted using ImageJ (bottom panel). (c) Skin was obtained from UVB-exposed MRL/lpr Fn14 WT and KO mice. Shown are representative images of CD3 stained sections from randomly selected 13–15 week old female UVB-irradiated MRL/lpr Fn14WT (n=7) and MRL/lpr Fn14KO mice (n=7) skin. The bottom panel shows the quantitation of CD3 staining; cells were counted in random 20× fields using ImageJ (WT, n=7; KO, n=7). The figures are representative of 2–3 independent experiments. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
Figure 2
Figure 2
UVB irradiation induces NGAL. (a) Nine to ten week old female MRL/lpr (n=4) and MRL/MpJ (n=4) mice were irradiated and skin lysates prepared as described above. Depicted in the graph are fold changes in NGAL concentrations compared to baseline, as measured by ELISA. The mean NGAL level in non-irradiated mice in each strain was arbitrarily set at 1. (b) Thirteen to fifteen week old female MRL/lpr Fn14WT (n=8) and Fn14KO (n=7) mice were irradiated, and NGAL in skin lysates analyzed as in (a). (c) Representative images of NGAL stained sections from randomly selected 13–15 week old female UVB-irradiated MRL/lpr Fn14WT (n=8) and Fn14KO mice (n=7). Quantitation of NGAL staining is provided in the right panel. The area with fluorescence was measured by ImageJ. *P<0.05, **P<0.01.
Figure 3
Figure 3
Macrophage depletion protects MRL/lpr mice from UVB-induced injury. Skin was obtained from UVB-exposed and non-exposed MRL/lpr Fn14 WT and KO mice. (a) Shown are representative images of IBA-1 stained sections from randomly selected 13–15 week old female UVB-irradiated MRL/lpr Fn14WT (n=11) and MRL/lpr Fn14KO mice (n=10). (b) Eight week old female MRL/lpr mice were treated with GW2580 via oral gavage for 16 days. During the last two days of GW2580 treatment, mice were exposed to UVB (50 mJ/cm2) and sacrificed 24 hours later. Shown are representative H&E images from GW (n=5) and PBS-treated (n=6) mice. The asterisk labels acanthotic epidermis, the arrowhead indicates parakeratosis, and the arrow points toward an epidermal pustule (left panel). (c) Representative H&E images of MRL/lpr Fn14WT (GW2580, n=3; PBS, n=2) and MRL/lpr Fn14KO mice (GW2580, n=3; PBS, n=2), treated and irradiated as above.
Figure 4
Figure 4
UVB irradiation induces production of proinflammatory chemokines. Ten week old female MRL/lpr mice were irradiated as described above. RNA was isolated from irradiated mice (n=5) and unmanipulated controls (n=5), and analyzed for various chemokines by PCR (top panel). Chemokine levels in skin lysates from irradiated MRL/lpr mice (n=5) and unmanipulated MRL/lpr controls (n=4) were measured using a flow cytometer based multiplex assay (bottom panel). *P<0.05, **P<0.01, ****P<0.0001.
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