TY - JOUR

T1 - Endogenous transforming growth factor-beta promotes quiescence of primary microglia in vitro

AU - Spittau, Björn

AU - Wullkopf, Lena

AU - Zhou, Xiaolai

AU - Rilka, Jennifer

AU - Pfeifer, Dietmar

AU - Krieglstein, Kerstin

N1 - Copyright © 2012 Wiley Periodicals, Inc.

PY - 2013/2

Y1 - 2013/2

N2 - 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 TGFβ1 results in increased microgliosis and neurodegeneration in mice which indicates that TGFβ1 is an important regulator of microglial functions in vivo. Here, we addressed the role of endogenous TGFβ signaling for microglia in vitro. We clearly demonstrate active TGFβ signaling in primary microglia and further introduce Klf10 as a new TGFβ target gene in microglia. Moreover, we provide evidence that microglia express and release TGFβ1 that acts in an autocrine manner to activate microglial TGFβ/Smad signaling in vitro. Using microarrays, we identified TGFβ-regulated genes in microglia that are involved in TGFβ1 processing, its extracellular storage as well as activation of latent TGFβ. Finally, we demonstrate that pharmacological inhibition of microglial TGFβ 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 TGFβ1 and autocrine TGFβ signaling is important for microglial quiescence in vitro and further suggest the upregulation of TGFβ1 in neurodegenerative diseases as a mechanism to regulate microglia functions and silence neuroinflammation.

AB - 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 TGFβ1 results in increased microgliosis and neurodegeneration in mice which indicates that TGFβ1 is an important regulator of microglial functions in vivo. Here, we addressed the role of endogenous TGFβ signaling for microglia in vitro. We clearly demonstrate active TGFβ signaling in primary microglia and further introduce Klf10 as a new TGFβ target gene in microglia. Moreover, we provide evidence that microglia express and release TGFβ1 that acts in an autocrine manner to activate microglial TGFβ/Smad signaling in vitro. Using microarrays, we identified TGFβ-regulated genes in microglia that are involved in TGFβ1 processing, its extracellular storage as well as activation of latent TGFβ. Finally, we demonstrate that pharmacological inhibition of microglial TGFβ 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 TGFβ1 and autocrine TGFβ signaling is important for microglial quiescence in vitro and further suggest the upregulation of TGFβ1 in neurodegenerative diseases as a mechanism to regulate microglia functions and silence neuroinflammation.

KW - Animals

KW - Animals, Newborn

KW - Brain

KW - Cells, Cultured

KW - Cytokines

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Microglia

KW - Oligonucleotide Array Sequence Analysis

KW - Protein Isoforms

KW - Receptors, Transforming Growth Factor beta

KW - Signal Transduction

KW - Smad Proteins

KW - Time Factors

KW - Transforming Growth Factor beta

U2 - 10.1002/glia.22435

DO - 10.1002/glia.22435

M3 - Journal article

C2 - 23065670

VL - 61

SP - 287

EP - 300

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 2

ER -