RNAi Silencing of HIF-1α Ameliorates Lupus Development in MRL/lpr Mice

Th17 cell and IL-17-mediated autoimmunity and inflammatory responses have been implicated in the development of organ damage in systemic lupus erythematosus (SLE), and new evidence suggests that hypoxia-inducible factor 1α (HIF-1α) enhances Th17 differentiation and promotes IL-17 production. However...

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Bibliographic Details
Published in:Inflammation 2018-10, Vol.41 (5), p.1717-1730
Main Authors: Zhao, Wei, Wu, Changhao, Li, Lian-Ju, Fan, Yin-Guang, Pan, Hai-Feng, Tao, Jin-Hui, Leng, Rui-Xue, Ye, Dong-Qing
Format: Article
Language:English
Subjects:
Animal models
Animals
Autoimmunity
Biomedical and Life Sciences
Biomedicine
Complement C3 - metabolism
Down-Regulation
Helper cells
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - physiology
Hypoxia-inducible factor 1a
Immunoglobulin G
Immunoglobulin G - metabolism
Immunology
Inflammation
Interleukin 17
Interleukin-17 - blood
Internal Medicine
Kidney - metabolism
Lupus
Lupus Erythematosus, Systemic - etiology
Lupus Erythematosus, Systemic - pathology
Lymphocytes T
Mice
Mice, Inbred MRL lpr
Original Article
Pathogenesis
Pathology
Pharmacology/Toxicology
Rheumatology
RNA Interference
RNA-mediated interference
Systemic lupus erythematosus
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Summary:Th17 cell and IL-17-mediated autoimmunity and inflammatory responses have been implicated in the development of organ damage in systemic lupus erythematosus (SLE), and new evidence suggests that hypoxia-inducible factor 1α (HIF-1α) enhances Th17 differentiation and promotes IL-17 production. However, the role of HIF-1α in the pathogenesis of lupus has not been examined. In this study, we silenced HIF-1α in vivo in a murine model of SLE to investigate whether lupus progression and the associated inflammatory pathways were affected by downregulating HIF-1α. Treatment with HIF1α-shRNA suppressed serum IL-17 level in MRL/lpr mice. Decreased anti-nucleosome antibody level, reduced urinary protein concentrations, ameliorated pathological damage, and remarkably reduced renal IgG and C3 depositions were observed in HIF1α-shRNA-treated group compared to those in the controls. Our results provide the first evidence for a role of HIF-1α in the pathogenesis of lupus and suggest a potential new therapeutic avenue for the treatment of lupus patients through reducing the HIF-1α level.
ISSN:0360-3997
1573-2576
DOI:10.1007/s10753-018-0815-6