TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis.
The cytokine TWEAK demonstrates potent kidney proinflammatory and proliferative effects. Recently, we have shown that interactions of TWEAK with its receptor Fn14 are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host (cGVH) induced model of lupus. Fn14 is expressed by macrophages and resident kidney cells; we hypothesized that TWEAK binding to both cell types contributes to the pathogenesis of lupus nephritis. To address this question, we generated bone marrow chimaeras and compared the progression of nephritis during cGVH induced lupus in mice expressing Fn14 only on bone marrow-derived cells, versus mice displaying Fn14 only on non-bone marrow-derived cells. While Fn14 deficiency did not significantly affect autoantibody titers, Fn14 deficiency on bone marrow-derived cells did not inhibit nephritis initiation in mice with Fn14 sufficient non-hematopoeitic cells. Conversely, expression of Fn14 only on bone marrow-derived cells resulted in a delayed, milder disease course. To further explore the role of macrophages, we depleted macrophages during cGVH induction. Surprisingly, we found that macrophage depleted mice displayed significantly increased titers of anti-DNA antibodies and worse kidney disease. We conclude that the presence of Fn14 on resident kidney cells alone may be sufficient to initiate nephritis in this murine model of lupus.
Molano
Alberto
A
The Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, United States.
Lakhani
Payal
P
Aran
Adi
A
Burkly
Linda C
LC
Michaelson
Jennifer S
JS
Putterman
Chaim
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D002678:Chimera; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000276:immunology* / Q000378:metabolism
D000974:Antibodies, Antinuclear; D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors