A possible mechanism of microglia-photoreceptor crosstalk

Li-ping Yang, Xiu-an Zhu, Mark O M Tso
Molecular Vision 2007, 13: 2048-57

PURPOSE: The goal of this study was to explore the relationship between photoreceptor apoptosis and retinal microglial activation.

METHODS: A murine photoreceptor cell line (661W cells) was exposed to LPS-treated microglial cell conditioned medium (MGCM), and cell viability was assessed by terminal dUTP transferase nick end labeling (TUNEL) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, microglia were exposed to culture media from light-damaged 661W photoreceptor cells (PRCM), and microglial activation was assessed morphologically by phase contrast microscopy. Reverse transcription polymerase chain reaction was used to examine mRNA levels of several chemokines and noxious factors in the MGCM-treated photoreceptor cells and the PRCM-treated microgial. Western blotting was used to analyze NF-kappaB p65 subunit, phosphorylated MAPKs p38, p44/42 (Erk1/2), and c-Jun N-terminal kinase (JNK).

RESULTS: Our results showed 37% of 661W cells underwent apoptosis following exposure to MGCM for 24 h. MGCM-induced death was associated with down-regulation of chemokine expression (i.e., eotaxin and RANTES), upregulation of inflammatory mediators (i.e., MIP-1alpha, MIP-1beta, IL-10, iNOS, and TNF-alpha), and increased phosphorylation of p38, p44/p42, and JNK. Retinal microglia acquired an activated phenotype after exposure to PRCM for 24 h. Microglial activation was accompanied by increased NF-kappaB p65 expression, increased phosphorylation of p38 and JNK, and upregulation of chemokines (i.e., eotaxin and RANTES) and inflammatory mediators (i.e., iNOS and IL-10).

CONCLUSIONS: Light-damaged photoreceptors release immunological signaling molecules that attract microglia, resulting in microglial activation and subsequent further degeneration of remaining photoreceptors. These results also suggest that p38, p44/42, and JNK may regulate glial-induced photoreceptor death and that p38, JNK, and NF-kappaB may regulate photoreceptor-induced microglial activation.

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