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Amphotericin B Increases Transglutaminase 2 Expression Associated with Upregulation of Endocytotic Activity in Mouse
Kenji Kawabe1, Katsura Takano2, Mitsuaki Moriyama1
1Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58, Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan.
Abstract:
Amphotericin B (AmB), a polyene antibiotic, is reported to cause the microglial activation to induce nitric oxide (NO) production and proinflammatory cytokines expression, and change neurotrophic factors expression in cultured microglia (Motoyoshi et al. in Neurochem Int 52:1290-1296, 2008). On the other hand, tissue-type transglutaminase (TG2) is involved in connection to phagocytes with apoptotic cells. Engulfment of neurons by activated microglia is thought to cause neurodegenerative diseases but detail is unclear, and involvement of TG2 in phagocytosis has been reported in our previous study using lipopolysaccharide-stimulated BV-2 cells (Kawabe et al. in Neuroimmunomodulation 22(4):243-249, 2015). In the present study, we examined the changes of TG2 expression, phagocytosis and pinocytosis in BV-2 cells stimulated by AmB. AmB stimulation increased TG2 expression and TG activity. Phagocytosis of dead cells and pinocytosis of fluorescent microbeads were also up-regulated by AmB stimulation in BV-2 cells. Blockade of TG activity by cystamine, an inhibitor of TGs, suppressed AmB-enhanced TG2 expression, TG activity, NO production, phagocytosis and pinocytosis. Excessive NO production from microglia and/or facilitation of phagocytosis might be involved in neuronal death. To control TG activity might make possible to protect neurons and care for CNS diseases.
Insights
Amphotericin B activates microglia, increasing tissue-type transglutaminase (TG2) and phagocytosis. Inhibiting TG2 protects neurons from AmB-induced damage, suggesting TG2 as a therapeutic target for CNS diseases.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Amphotericin B (AmB) activates microglia, inducing nitric oxide (NO) and inflammatory cytokines.
- Tissue-type transglutaminase (TG2) links phagocytes to apoptotic cells, and its role in microglial phagocytosis is under investigation.
- Microglial engulfment of neurons is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the effects of AmB on TG2 expression, phagocytosis, and pinocytosis in BV-2 microglial cells.
- To determine if TG2 activity mediates AmB-induced microglial responses.
Main Methods:
- BV-2 cells were stimulated with AmB.
- TG2 expression and activity were measured.
- Phagocytosis of dead cells and pinocytosis of fluorescent microbeads were assessed.
- The effects of cystamine, a TG inhibitor, were evaluated.
Main Results:
- AmB stimulation increased TG2 expression and activity in BV-2 cells.
- AmB enhanced both phagocytosis of dead cells and pinocytosis.
- Cystamine treatment suppressed AmB-induced increases in TG2, NO production, phagocytosis, and pinocytosis.
Conclusions:
- AmB-induced microglial activation involves increased TG2 expression and activity.
- TG2 plays a role in AmB-mediated phagocytosis and pinocytosis.
- Inhibition of TG2 may offer neuroprotection against AmB-induced damage, highlighting TG2 as a potential therapeutic target for central nervous system diseases.
