TIMP-1 couples RhoK activation to IL-1β-induced astrocyte responses

Abstract

Interleukin-1β (IL-1β) is a pleotropic cytokine known to influence the central nervous system (CNS) responses to injury or infection. IL-1β also directly induces astrocytic expression of tissue inhibitor of metalloproteinases (TIMP)-1, a potent trophic factor and regulator of matrix metalloproteinase activity. In this study, we examined the functional relationship between IL-1β and TIMP-1 and determined that the behavior of astrocytes in response to IL-1β is determined by TIMP-1 expression. Using primary astrocytes from C57Bl/6 mice, we found astrocytes from wildtype (Wt) mice exhibited a robust wound healing response to a scratch wound that was arrested in response to IL-1β. In contrast, TIMP-1 knockout (TIMP-1KO) astrocytes, exhibited minimal response to the scratch wound but an accelerated response following IL-1β-treatment. We also determined that the scratch wound effect in Wt cultures was attenuated by inhibition of Rho kinase but amplified in the TIMP-1KO cultures. We propose that the specific induction of TIMP-1 from astrocytes in response to IL-1β reflects a previously unrecognized physiological relationship where the directionality of astrocytic behavior is determined by the actions of TIMP‑1. These findings may provide additional insight into glial responses in the context of neuropathology where expression of TIMP-1 may vary and astrocytic responses may be impacted by the inflammatory milieu of the CNS.

Keywords: Astrocyte; IL-1β; MMP; ROCK; TIMP-1.