Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model.

Autor: Lee JW; Microbiology, Department of Oral Pathobiological Science, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan. jwlee@den.hokudai.ac.jp., Mizuno K; Microbiology, Department of Oral Pathobiological Science, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan.; Dentistry for Children and Disabled Persons, Department of Oral Functional Science, Faculty of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Watanabe H; Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan.; Oral Diagnosis and Medicine, Department of Oral Pathobiological Science, Faculty of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Lee IH; Computational Health and Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA., Tsumita T; Department of Vascular Biology and Molecular Pathology, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Hida K; Department of Vascular Biology and Molecular Pathology, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Yawaka Y; Dentistry for Children and Disabled Persons, Department of Oral Functional Science, Faculty of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Kitagawa Y; Oral Diagnosis and Medicine, Department of Oral Pathobiological Science, Faculty of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Hasebe A; Microbiology, Department of Oral Pathobiological Science, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Iimura T; Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University, Kita13 Nishi7, Kita-Ku, Sapporo, 060-8586, Japan., Kong SW; Computational Health and Informatics Program, Boston Children's Hospital, Boston, MA, 02215, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Aug 06; Vol. 21 (1), pp. 196. Date of Electronic Publication: 2024 Aug 06.
DOI: 10.1186/s12974-024-03192-7
Abstrakt: Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.
(© 2024. The Author(s).)
Databáze: MEDLINE
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