Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus mouse model via inhibition of the TWEAK/Fn14 Pathway.
BACKGROUND
Systemic lupus erythematosus (SLE) is an autoimmune-mediated chronic inflammatory disease. Half of patients with SLE suffer from lupus nephritis, which is major cause of death in SLE. TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) interactions mediate inflammatory responses that are linked to the pathogenesis of lupus nephritis. Blocking of the TWEAK/Fn14 pathway by Fn14-Fc was performed in a SLE mouse model and the likely therapeutic mechanisms were investigated.


METHODS
To investigate the impact of TWEAK on B cell differentiation in SLE, the levels of AID, Blimp-1, and IRF4 messenger RNA were measured in CD19(+) B cells extracted from the spleens of sanroque mice and cultured with TWEAK. To identify the therapeutic effects of Fn14-Fc in SLE, sanroque mice were treated with Fn14-Fc or a control-Fc for 3 weeks. Immunoglobulin (Ig) G, IgG1, IgG2a, and anti-dsDNA antibody (Ab) levels were measured in the sera of each group. Spleens from each group were stained with antibodies against CD4, B220, GL-7, CD138, and PD-1. Kidneys were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS).


RESULTS
Administration of TWEAK increased the mRNA levels of AID, Blimp-1, and IRF4. Treatment with Fn14-Fc suppressed levels of IgG, IgG1, IgG2a, and anti-dsDNA Ab in sera and reduced numbers of B, plasma, and follicular helper T (Tfh) cells in spleens of sanroque mice. In addition, renal protective effects of Fn14-Fc were shown.


CONCLUSIONS
Fn14-Fc had beneficial effects in a SLE mouse model by repressing B cells, plasma cells, Tfh, and renal damage. This suggested that Fn14-Fc represents a potential therapeutic agent for SLE.
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.|Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Hong-Ki
HK
Min
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Sung-Min
SM
Kim
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Jin-Sil
JS
Park
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Jae-Kyeong
JK
Byun
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.|Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Jennifer
J
Lee
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.|Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Seung-Ki
SK
Kwok
Integrative Omics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, South Korea.
Young-Woo
YW
Park
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea.
Mi-La
ML
Cho
Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea. rapark@catholic.ac.kr.|Division of Rheumatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 137-701, South Korea. rapark@catholic.ac.kr.
Sung-Hwan
SH
Park
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D002454:Cell Differentiation; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D018858:Germinal Center / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D011961:Receptors, Fc / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism*
D000074049:Cytokine TWEAK; D007136:Immunoglobulins; D011961:Receptors, Fc; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
Fibroblast growth factor-inducible 14 (Fn14); Follicular helper T (Tfh) cell; Germinal center (GC); Systemic lupus erythematosus (SLE); TNF-like weak inducer of apoptosis (TWEAK)