IRAK4 is an immunological checkpoint in neuropsychiatric systemic lupus erythematosus.

Autor: Ménoret A; Department of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA. menoret@uchc.edu., Agliano F; Department of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA., Karginov TA; Department of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA., Hu X; Department of Neuroscience, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA., Vella AT; Department of Immunology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA. vella@uchc.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 16; Vol. 14 (1), pp. 16393. Date of Electronic Publication: 2024 Jul 16.
DOI: 10.1038/s41598-024-63567-x
Abstrakt: The search for dementia treatments, including treatments for neuropsychiatric lupus (NPSLE), has not yet uncovered useful therapeutic targets that mitigate underlying inflammation. Currently, NPSLE's limited treatment options are often accompanied by severe toxicity. Blocking toll-like receptor (TLR) and IL-1 receptor signal transduction by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4) offers a new pathway for intervention. Using a pre-clinical NPSLE model, we compare lupus-like B6.MRL-Faslpr (MRL) mice with B6.MRL-Faslpr-IRAK4 kinase-dead (MRL-IRAK4-KD) mice, which are were less prone to 'general' lupus-like symptoms. We demonstrate that lupus-prone mice with a mutation in the kinase domain of IRAK4 no longer display typical lupus hallmarks such as splenomegaly, inflammation, production of hormones, and anti-double-stranded (ds)DNA antibody. water maze behavioral testing, which measures contextual associative learning, revealed that mice without functional IRAK4 displayed a recovery in memory acquisition deficits. RNA-seq approach revealed that cytokine and hormone signaling converge on the JAK/STAT pathways in the mouse hippocampus. Ultimately, the targets identified in this work may result in broad clinical value that can fill the significant scientific and therapeutic gaps precluding development of cures for dementia.
(© 2024. The Author(s).)
Databáze: MEDLINE
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