Activated alpha2-macroglobulin induces Muller glial cell migration by regulating MT1-MMP activity through LRP1

BARCELONA, PABLO F.; JALDÍN-FINCATI, JAVIER R.; SÁNCHEZ, MARÍA C.; CHIABRANDO, GUSTAVO A.

FASEB Journal

FASEB

Año: 2013 vol. 27 p. 3181 - 3197

In retinal proliferative diseases, Müller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloprotease 2 (MMP-2) and MMP-9 also present increased levels of the protease inhibitor α22-macroglobulin (α22M) and its receptor, the low-density lipoprotein receptorrelated protein 1 (LRP1). In the present work, we investigated whether the protease activated form of α22M, α2 2M*, and LRP1 are involved with the MGC migratory process. By performing wound-scratch migration and zymography assays, we demonstrated that α22M*induced cell migration and proMMP-2 activation in the human Müller glial cell line, MIO-M1. This induction was blocked when LRP1 and MT1-MMP were knocked down with siRNA techniques. Using fluorescence microscopy and biochemical procedures, we found that 2M*induced an increase in LRP1 and MT1-MMP accumulation in early endosomes, followed by endocytic recycling and intracellular distribution of MT1-MMP toward cellular protrusions. Moreover, Rab11-dominant negative mutant abrogated MT1-MMP recycling pathway, cell migration, and proMMP-2 activation induced by α22M*. In conclusion, α22M*, through its receptor LRP1, induces cellular migration of Müller glial cells by a mechanism that involves MT1-MMP intracellular traffic to the plasma membrane by a Rab11-dependent recycling pathway. © FASEB.