Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro.

ABSTRACT

Microglia are the immune cells of the central nervous system (CNS) and play important roles under physiological and pathophysiological conditions. Activation of microglia has been reported for a variety of CNS diseases and is believed to be involved in inflammation-mediated neurodegeneration. Loss of TGFß1 results in increased microgliosis and neurodegeneration in mice which indicates that TGFß1 is an important regulator of microglial functions in vivo. Here, we addressed the role of endogenous TGFß signaling for microglia in vitro. We clearly demonstrate active TGFß signaling in primary microglia and further introduce Klf10 as a new TGFß target gene in microglia. Moreover, we provide evidence that microglia express and release TGFß1 that acts in an autocrine manner to activate microglial TGFß/Smad signaling in vitro. Using microarrays, we identified TGFß-regulated genes in microglia that are involved in TGFß1 processing, its extracellular storage as well as activation of latent TGFß. Finally, we demonstrate that pharmacological inhibition of microglial TGFß signaling resulted in upregulation of the proinflammatory markers IL6 and iNOS and downregulation of the alternative activation markers Arg1 and Ym1 in vitro. Together, these data clearly show that endogenous TGFß1 and autocrine TGFß signaling is important for microglial quiescence in vitro and further suggest the upregulation of TGFß1 in neurodegenerative diseases as a mechanism to regulate microglia functions and silence neuroinflammation.