Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Abstract

In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss-and gainof-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.brain damage | astrogliosis A strocytes are the most abundant cell type in the mammalian brain. The thin processes of protoplasmic astrocytes (graymatter astrocytes) canvas the neural parenchyma and make contact with several other cell types. Protoplasmic astrocytes carry out a variety of functions, including maintaining the bloodbrain barrier, ion homeostasis, neurotransmitter turnover, and synapse formation (1). Another major function of these astrocytes involves their activation in response to damage. Astrocyte activation, or astrogliosis, plays a central role in the response to most or all neurological insults including trauma, infections, stroke, tumorigenesis, neurodegeneration, and epilepsy. The extent of astrogliosis can influence long-term recovery, and the response of astrocytes to different insults is likely to be graded and complex (2, 3). Nevertheless, in most cases, astrocytes transiently become hypertrophic and express high levels of intermediate filaments such as GFAP, vimentin, tenascin C, and nestin, and, in cases of severe damage, astrocytes can also become proliferative and form a scar.Astrogliosis can have beneficial and detrimental effects on recovery. Astrogliosis is essential for minimizing the spread of damage and inflammation, but it is also inhibitory for axonal and cellular regeneration. For example, in transgenic mice in which reactive astrocytes are ablated or disabled, traumatic injury leads to the lack of normal scar formation, prolonged and more widespread inflammation, and a failure to reconstruct the bloodbrain barrier and maintain tissue integrity (4, 5). However, ablation or impairment of reactive astrocytes also leads to increased nerve fiber growth in the immediate vicinity of the injury site, which could improve axonal regeneration and functional recovery (4, 5). Therefore, levels of astrocy...

Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

“…However, FGF-2 also inhibited the TGF-␤1-mediated increase of GFAP expression in astrocytes (44). A recent study demonstrated that the loss of the FGF-2 receptor in astrocytes induced astrocyte activation in unperturbed mice, suggesting that FGF signaling in astrocytes is required to maintain their nonreactive state (36). In this study, we have confirmed the activated effects of neurons on astrocyte and the related signaling (supplemental Fig.…”

“…This study has revealed that the inactivation of mTORC1 in postmitotic neurons causes moderate reactive astrogliosis. The loss of neural mTORC1 activity may induce astrogliosis by reducing the neuronal secretion of FGF-2, thereby inhibiting FGF receptor signaling in astrocytes, which is required to maintain their nonreactive state (36) (Fig. 7).…”

“…Although the importance of FGF signaling in CNS development is well established, the role of FGF-2 in astrogliosis remains controversial (17,36,44). FGF-2 was shown to induce astroglial and microglial reactivity in the rat brain (45) and mediate the morphogenesis of Drosophila astrocytes during development (17).…”

Neurotoxic reactive astrocytes are induced by activated microglia

“…As a proof of principal, we also investigated if additional molecules could revert A1s to a non-reactive phenotype. We tested the anti-inflammatory cytokine TGFβ and FGF (as it has been previously shown that astrocyte activation is suppressed in the injured brain by FGF signaling 19 ). We grew A1s in culture, then treated with TGFβ or FGF and found both significantly decreased reactive astrocyte transcript levels (Fig.…”

FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation

“…Transfection of tyrosine kinase-deleted FGFR1 into rat SN has been shown to significantly reduce the number of dopaminergic neurons in SN and the dopamine level in striatum [15]. Moreover, it has recently been reported that FGF signaling is required for astrocytes to maintain their nonreactive state under physiological conditions and suppress their activation after injury [16]. Accordingly, the downstream intracellular signaling pathways of FGFRs are also diverse, including Ras/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K)/AKT, and phospholipase Cγ (PLCγ) [17].…”