Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice

Hui Yang Zeng, Xiu An Zhu, Cheng Zhang, Li Ping Yang, Le Meng Wu, Mark O M Tso

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

PURPOSE. To elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. METHODS. Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-γ-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)-α in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF-α was determined by double immunolabeling. RESULTS. Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES transcripts were noted at P8 and reached a peak at Pl2. Production of TNF-α was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF-α was predominantly expressed in the activated microglial cells in the ONL. CONCLUSIONS. Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-α), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-α, produced by the activated microglia, may accentuate the photoreceptor cell death.

Original languageEnglish (US)
Pages (from-to)2992-2999
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number8
DOIs
StatePublished - 2005
Externally publishedYes

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Retinal Degeneration
Macrophage Inflammatory Proteins
Microglia
Chemokine CCL7
Tumor Necrosis Factor-alpha
Chemokine CCL2
Chemokines
Apoptosis
Photoreceptor Cells
T-Lymphocytes
Retina
Chemokine CX3CL1
Chemokine CXCL10
Poisons
Transferases
Reverse Transcription
Cell Movement
Cell Death
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice. / Zeng, Hui Yang; Zhu, Xiu An; Zhang, Cheng; Yang, Li Ping; Wu, Le Meng; Tso, Mark O M.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 8, 2005, p. 2992-2999.

Research output: Contribution to journalArticle

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title = "Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice",
abstract = "PURPOSE. To elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. METHODS. Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-γ-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)-α in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF-α was determined by double immunolabeling. RESULTS. Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES transcripts were noted at P8 and reached a peak at Pl2. Production of TNF-α was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF-α was predominantly expressed in the activated microglial cells in the ONL. CONCLUSIONS. Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-α), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-α, produced by the activated microglia, may accentuate the photoreceptor cell death.",
author = "Zeng, {Hui Yang} and Zhu, {Xiu An} and Cheng Zhang and Yang, {Li Ping} and Wu, {Le Meng} and Tso, {Mark O M}",
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T1 - Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice

AU - Zeng, Hui Yang

AU - Zhu, Xiu An

AU - Zhang, Cheng

AU - Yang, Li Ping

AU - Wu, Le Meng

AU - Tso, Mark O M

PY - 2005

Y1 - 2005

N2 - PURPOSE. To elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. METHODS. Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-γ-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)-α in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF-α was determined by double immunolabeling. RESULTS. Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES transcripts were noted at P8 and reached a peak at Pl2. Production of TNF-α was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF-α was predominantly expressed in the activated microglial cells in the ONL. CONCLUSIONS. Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-α), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-α, produced by the activated microglia, may accentuate the photoreceptor cell death.

AB - PURPOSE. To elucidate the role of activated microglia in the photoreceptor apoptosis of rd mice by identifying sequential events and factors associated with microglial activation, migration, and cytotoxicity during retinal degeneration. METHODS. Photoreceptor apoptosis in rd mice at postnatal days (P)8, 10, 12, 14, 16, and 18 was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglia were identified by CD11b antibody. Expression of chemokine mRNA, including monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation normal T-cell expressed and secreted (RANTES), interferon-γ-inducible 10-kDa protein (IP-10), and fractalkine in the retina were examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. Production of tumor necrosis factor (TNF)-α in the dystrophic retina was studied by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry analysis. Microglial expression of TNF-α was determined by double immunolabeling. RESULTS. Whereas photoreceptor apoptosis in the rd mice started at P10 and reached a peak at P16, activation and migration of microglial cells were observed at P10 and peaked at P14. The expression of MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES transcripts were noted at P8 and reached a peak at Pl2. Production of TNF-α was noted in the outer nuclear layer (ONL) of the rd mice at P8 and reached a peak at P12. At the peak of microglial activity, TNF-α was predominantly expressed in the activated microglial cells in the ONL. CONCLUSIONS. Activation of microglia, as well as expression of their signaling molecules (chemokines) and microglia-derived toxic factor (TNF-α), coincides with or precedes the occurrence of photoreceptor apoptosis, suggesting activated microglia play a major role in retinal degeneration in rd mice. The chemokines MCP-1, MCP-3, MIP-1α, MIP-1β, and RANTES are involved in activation and recruitment of the microglia to the degenerating photoreceptor cell layer. TNF-α, produced by the activated microglia, may accentuate the photoreceptor cell death.

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U2 - 10.1167/iovs.05-0118

DO - 10.1167/iovs.05-0118

M3 - Article

VL - 46

SP - 2992

EP - 2999

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

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