Alpha2-Macroglobulin induces glial fibrillary acidic protein mediated by LRP1 in retinal Muller cells.

BARCELONA P; ORTIZ S; CHIABRANDO G; SANCHEZ MC

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE

ASSOC RESEARCH VISION OPHTHALMOLOGY INC

Año: 2011 vol. 52 p. 778 - 786

0146-0404

Purpose: Although it is known that M¨¹ller cells express the glial fibrillary acidic protein (GFAP) in response to acute retinal damage, the regulatory mechanism is not completely understood. ¦Á2-macroglobulin (¦Á2M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), have also been found in injured retinas. Herein, we examined the involvement of the ¦Á2M/LRP1 system in GFAP expression in M¨¹ller cells using in vitro and in vivo experimental models. Methods: Using Western blot and immunocytochemistry, we evaluated the effect of ¦Á2M* on the GFAP expression in the M¨¹ller cell line MIO-M1, which constitutively expresses LRP1. Intracellular signaling pathways activated by ¦Á2M* were examined by Western blot. The effect of ¦Á2M* on the GFAP expression in the mouse retina was examined by intravitreal microinjection of ¦Á2M* in mouse eyes. Results: Our data demonstrate that ¦Á2M* induced GFAP expression in the MIO-M1 cell line, which was selectively blocked by RAP, an antagonist of LRP1 binding ligands. In addition, ¦Á2M* induced JAK/STAT pathway activation, determined by STAT3 phosphorylation (p-STAT3), which was also blocked by RAP. Finally, we showed that GFAP was expressed in the retina of mice, preferentially in M¨¹ller cells at 3 and 6 days after a single intravitreal ¦Á2M* injection, whereas p-STAT3 staining increased at day 1 in both the ganglion cell layer and the inner nuclear layer. Conclusions: These results demonstrate that ¦Á2M* induces GFAP expression in retinal M¨¹ller cells through LRP1, which could be mediated by JAK/STAT pathway activation.