期刊
FRONTIERS IN IMMUNOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.903309
关键词
LPS; NLRP3; Akt; microglia; FAK; varlitinib; tau; DYRK1A
类别
资金
- KBRI basic research program through KBRI - Ministry of Science, ICT & Future Planning [22-BR-02-03, 22-BR03-05, 22- BR- 04- 01]
- National Research Foundation of Korea [2019R1A2B5B01070108 H-SH, 2021R1F1A1057865]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute ( KHIDI) - Ministry of Health & Welfare, Republic of Korea [HF21C0021]
- National Research Council of Science & Technology (NST) - Korean government [CCL22061-100]
- National Research Foundation of Korea [2021R1F1A1057865] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
This study demonstrates the therapeutic potential of varlitinib in inhibiting neuroinflammatory responses induced by LPS and tau, providing insights into the underlying mechanisms.
The FDA-approved EGFR/HER2 inhibitor varlitinib inhibits tumor growth and is used in cancer treatment. However, the neuroinflammatory response associated with EGFR/HER2 and its underlying mechanism have not been elucidated. This study evaluates the impact of varlitinib on LPS- and tau-mediated neuroinflammatory responses for the first time. In BV2 microglial cells, varlitinib reduced LPS-stimulated il-1 beta and/or inos mRNA levels and downstream AKT/FAK/NF-kB signaling. Importantly, varlitinib significantly diminished LPS-mediated microglial nlrp3 inflammasome activation in BV2 microglial cells. In primary astrocytes, varlitinib downregulated LPS-evoked astroglial il-1 beta mRNA levels, AKT signaling, and nlrp3 inflammasome activation. In LPS-treated wild-type mice, varlitinib significantly reduced LPS-stimulated glial activation and IL-1 beta/NLRP3 inflammasome formation. Moreover, varlitinib significantly reduced micro- and astroglial activation and tau hyperphosphorylation in 3-month-old tau-overexpressing PS19 mice by downregulating tau kinase DYRK1A levels. However, in 6-month-old tau-overexpressing PS19 mice, varlitinib only significantly diminished astroglial activation and tau phosphorylation at Thr212/Ser214. Taken together, our findings suggest that varlitinib has therapeutic potential for LPS- and tau-induced neuroinflammatory responses and the early stages of tau pathology.
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