title: alpha2-Macroglobulin induces glial fibrillary acidic protein expression mediated by low-density lipoprotein receptor-related protein 1 in Müller cells.
abstract: OBJECTIVE
  Although it is known that Müller cells express the glial fibrillary acidic protein (GFAP) in response to acute retinal damage, the regulatory mechanism is not completely understood. α(2)-Macroglobulin (α(2)M) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have also been found in injured retinas. Herein, the authors examined the involvement of the α(2)M/LRP1 system in GFAP expression in Müller cells using in vitro and in vivo experimental models.
  
  
  METHODS
  Using Western blot analysis and immunocytochemistry, the authors evaluated the effect of α(2)M* on GFAP expression in the Müller cell line MIO-M1, which constitutively expresses LRP1. Intracellular signaling pathways activated by α(2)M* were examined by Western blot analysis. The effect of α(2)M* on GFAP expression in the mouse retina was examined by intravitreal microinjection of α(2)M* in mouse eyes.
  
  
  RESULTS
  These data demonstrate that α(2)M* induced GFAP expression in the MIO-M1 cell line, which was selectively blocked by RAP, an antagonist of LRP1 binding ligands. In addition, α(2)M* induced JAK/STAT pathway activation, determined by STAT3 phosphorylation (p-STAT3), which was also blocked by RAP. Finally, the authors showed that GFAP was expressed in the retinas of mice, preferentially in Müller cells at 3 and 6 days after a single intravitreal α(2)M* 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 α(2)M* induces GFAP expression in retinal Müller cells through LRP1, which could be mediated by JAK/STAT pathway activation.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Barcelona
authors.forename: Susana G
authors.initials: SG
authors.lastname: Ortiz
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Chiabrando
authors.forename: Maria C
authors.initials: MC
authors.lastname: Sánchez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000494:pharmacology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D025521:Tumor Suppressor Proteins; D014746:Vimentin; D000511:alpha-Macroglobulins; D053612:Janus Kinases