Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease

Autor: Ryusuke Yoshimi, Tadatsugu Taniguchi, Hideyuki Yanai, Shuichi Suzuki, Akira Nishiyama, Hideaki Nakajima, Tadashi Yamamoto, Shuichi Ito, Kappei Tsukahara, Yohei Kirino, Noriko Tagata, Go R. Sato, Kenichi Nishimura, Tatsuma Ban, Hiroe Hihara, Masako Kikuchi, Akio Manabe, Masashi Ito, Kentaro Yoshimatsu, Yoshiko Matsumoto, Kayo Harita, Tomohiko Tamura
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
PATHOGENESIS
INTERFERON REGULATORY FACTOR
General Physics and Astronomy
PROTECTS MICE
Autoimmunity
Disease
Receptor
Interferon alpha-beta
medicine.disease_cause
Kidney
Mice
0302 clinical medicine
Interferon
immune system diseases
Lupus Erythematosus
Systemic
skin and connective tissue diseases
Innate immunity
Mice
Knockout
Multidisciplinary
Systemic lupus erythematosus
DEFICIENCY
src-Family Kinases
PLASMA-CELLS
B-CELLS
Interferon Regulatory Factors
Female
Signal transduction
medicine.drug
Signal Transduction
ERYTHEMATOSUS
Science
DENDRITIC CELLS
General Biochemistry
Genetics and Molecular Biology
Article
Target validation
Autoimmune Diseases
03 medical and health sciences
medicine
Animals
Humans
Autoantibodies
030203 arthritis & rheumatology
Autoimmune disease
Lupus erythematosus
business.industry
General Chemistry
medicine.disease
Immunity
Innate
Mice
Inbred C57BL
030104 developmental biology
Gene Expression Regulation
Immunoglobulin G
Cancer research
ALPHA ACTIVITY
business
IRF5
Transcription Factors
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
ISSN: 2041-1723
Popis: The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.
IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.
Databáze: OpenAIRE
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