Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses.

Abstract

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of <i>Timp1</i> do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global <i>Timp1</i> knockout (<i>Timp1</i>^KO) mice do not efficiently remyelinate following a demyelinating injury. Here, we performed an unbiased proteomic analysis and identified a fibronectin-derived peptide called Anastellin (Ana) that was unique to the <i>Timp1</i>^KO astrocyte secretome. Ana was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Ana is known to act upon the sphingosine-1-phosphate receptor 1, and we determined that Ana also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation <i>in vitro.</i> Administration of FTY720 to wild-type C57BL/6 mice during MOG_35-55-experimental autoimmune encephalomyelitis ameliorated clinical disability while FTY720 administered to mice lacking expression of <i>Timp1</i> (<i>Timp1</i>^KO) had no effect. Analysis of <i>Timp1</i> and fibronectin (<i>FN1</i>) transcripts from primary human astrocytes from healthy and multiple sclerosis (MS) donors revealed lower <i>TIMP1</i> expression was coincident with elevated <i>FN1</i> in MS astrocytes. Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.