Fn14 deficiency protects lupus-prone mice from histological lupus erythematosus-like skin inflammation induced by ultraviolet light.
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.
The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Jessica
J
Doerner
The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Samantha A
SA
Chalmers
Department of Dermatology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Adam
A
Friedman
The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.|Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA.
Chaim
C
Putterman
D000818:Animals; D017209:Apoptosis; D018925:Chemokines / Q000378:metabolism; D000074049:Cytokine TWEAK / Q000378:metabolism; D005260:Female; D000071068:Lipocalin-2 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000150:complications*; D018345:Mice, Knockout; D010787:Photosensitivity Disorders / Q000209:etiology* / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D000074050:TWEAK Receptor / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D018925:Chemokines; D000074049:Cytokine TWEAK; D000071068:Lipocalin-2; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; C071332:Lcn2 protein, mouse
MRL-lpr/lpr; TNF-like weak inducer of apoptosis; cutaneous lupus; macrophages; photosensitivity