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Tian Zhou; Alpha-1 antitrypsin ameliorates retinal degeneration by modulating microglia polarization in rd1 mice model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):773.
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© ARVO (1962-2015); The Authors (2016-present)
Alpha-1 antitrypsin (AAT) recently was proved to be a promising therapy in autoimmune diseases and transplantation by anti-inflammation. This study aimed to explore the therapeutic potential and mechanism of AAT for attenuating neuroinflammation and retinal degeneration in the rd1 mice.
For treatment, rd1 (Pde6brd1/rd1) mice received intraperitoneal injections of AAT 80mg/kg every other day from P4 to P14. Mice were sacrificed at P16 and eyes were enucleated for further investigation. The retinal degeneration condition was monitored by ERG, OCT and histology. The microglia maker Iba-1, polarization markers of M1 (iNOS, CD16/32) and M2 (Arg1, CD206), as well as other pro-inflammatory cytokines were evaluated by immunofluorescent staining, qPCR, and Western blot analysis.
AAT supplement preserved retinal structure of rd1 mice with preserved ONL, ELM, and IS/OS junction layers in OCT analysis, and histologic analysis confirmed the elevation of retinal thickness in AAT-treated retinae with increased amount of cellular nuclei in the ONL. Recognizable a- and b- waves were also recovered after AAT supplement. Mechanically, AAT shifted the microglia phenotype from CD16/CD32+ and iNOS+ M1 to CD206+ and Arg1+ M2 both in vivo and in vitro, underscoring the concept of immumodulation on microglia polarization by AAT. Furthermore, AAT suppressed IRF8 and increased IRF4 expression, with reduced STAT1 phosphorylation, indicating the involvement of these signaling pathways in microglia-mediated neuroinflammation.
Our findings revealed a novel neuroprotective role of AAT via immunomodulation on microglia polarization in rd1 model and IRF8/STAT4 bias was involved in AAT regulation. Thus, AAT emerged as an effective candidate for treating retinitis pigmentosa.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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