AUTHOR=Kim Jieun , Kim Su-Jin , Jeong Ha-Ram , Park Jin-Hee , Moon Minho , Hoe Hyang-Sook 

TITLE=Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.903309

DOI=10.3389/fimmu.2022.903309

ISSN=1664-3224

ABSTRACT=<p>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 <italic>il-1β</italic> and/or <italic>inos</italic> mRNA levels and downstream AKT/FAK/NF-kB signaling. Importantly, varlitinib significantly diminished LPS-mediated microglial <italic>nlrp3</italic> inflammasome activation in BV2 microglial cells. In primary astrocytes, varlitinib downregulated LPS-evoked astroglial <italic>il-1β</italic> mRNA levels, AKT signaling, and <italic>nlrp3</italic> inflammasome activation. In LPS-treated wild-type mice, varlitinib significantly reduced LPS-stimulated glial activation and IL-1β/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.</p>