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Review
. 2023 Mar 28;24(7):6321.
doi: 10.3390/ijms24076321.

Glia-Neurotrophic Factor Relationships: Possible Role in Pathobiology of Neuroinflammation-Related Brain Disorders

Ewelina Palasz  1 , Anna Wilkaniec  1 , Luiza Stanaszek  1 , Anna Andrzejewska  1   2 , Agata Adamczyk  1
Affiliations
Review

Glia-Neurotrophic Factor Relationships: Possible Role in Pathobiology of Neuroinflammation-Related Brain Disorders

Ewelina Palasz et al. Int J Mol Sci. .

Abstract

Neurotrophic factors (NTFs) play an important role in maintaining homeostasis of the central nervous system (CNS) by regulating the survival, differentiation, maturation, and development of neurons and by participating in the regeneration of damaged tissues. Disturbances in the level and functioning of NTFs can lead to many diseases of the nervous system, including degenerative diseases, mental diseases, and neurodevelopmental disorders. Each CNS disease is characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation, dysregulation of NTFs levels, or mitochondrial dysfunction. It has been shown that NTFs can control the activation of glial cells by directing them toward a neuroprotective and anti-inflammatory phenotype and activating signaling pathways responsible for neuronal survival. In this review, our goal is to outline the current state of knowledge about the processes affected by NTFs, the crosstalk between NTFs, mitochondria, and the nervous and immune systems, leading to the inhibition of neuroinflammation and oxidative stress, and thus the inhibition of the development and progression of CNS disorders.

Keywords: glial cells; mitochondrial dysfunction; neuroinflammation; neuroprotection; neurotrophic factors; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Microglia are activated by pathogen-associated molecular pattern molecules (PAMPs) and/or damage-associated molecular pattern molecules (DAMPs). The classical M1 activation can be induced by interferon-γ (IFN-γ) and lipopolysaccharide (LPS). M1 microglia produce inflammatory cytokines and chemokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, IL-12, and CC chemokine ligand (CCL) 2, and induce inflammation and neurotoxicity. The alternative M2 activation is induced by anti-inflammatory cytokines such as IL-4, IL-13, and IL-10. M2 microglia release growth factors (GFs), and neurotrophic factors (NTFs), induce mannose receptor (CD206) and arginase 1 (Arg1), and promote neuronal survival. Shifting from M1 to M2 phenotype may occur via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT) transcription factors, and activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. The figure was created with BioRender.com.
Figure 2
Figure 2
Reactive astrocytes are induced by classically activated neuroinflammatory microglia via secretion of interleukin (IL)-1α, IL-1β, tumor necrosis factor-alpha (TNF-α), and complement component 1q (c1q). Astrocytes show dual nature. The signaling molecules involved in the induction of pro-inflammatory A1 astrocytes are nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription 3 (STAT3), circlgf1r, Kir6.2, and microRNA2, while signaling molecules responsible for the induction of A2 astrocytes are phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), STAT3, tropomyosin receptor kinase B (TrkB), connexin30, chemokine receptor 7 (CXCR7), 17β-estradiol, fibroblast growth factor (FGF), milk fat globule epidermal growth factor 8 (MFG8), and transforming growth factor-β (TGF-β). A1 astrocytes release interleukin (IL)-1β, TNF-α, and C3 components to propagate the neuroinflammatory response. They also release D-serine and nitric oxide (NO), which may contribute to excitotoxicity. A2 astrocytes appear to release anti-inflammatory compounds, such as neurotrophic factors (NTFs), IL-10, IL-6, and TGF-β, and promote the survival and growth of neurons and reparative functions. The figure was created with BioRender.com.
Figure 3
Figure 3
Signaling cascades activated by neurotrophic factors (NTFs). The precursor of brain-derived neurotrophic factor (proBDNF) or nerve growth factor (NGF) binding the p75NTR leads to activation of c-Jun N-terminal kinase (JNK) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signaling pathways, which promote processes such as apoptosis and neuronal survival. The mature brain-derived neurotrophic factor/tropomyosin receptor kinase B (mBDNF/TrkB), NGF/tropomyosin receptor kinase A (TrkA), and glial cell-derived neurotrophic factor/GDNF family receptor α1/ receptor tyrosine kinase rearranged during transfection (GDNF/GFRα1-RET) complexes trigger activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), and phospholipase C-γ (PLC-γ) pathways that, in turn, activate the cAMP response element-binding protein (CREB) and transcription of genes responsible for development and survival of neurons. Cerebral dopamine neurotrophic factor (CDNF) receptors and CDNF-activated signaling pathways are still poorly understood, but the mechanism of CDNF action is associated mainly with the regulation of endoplasmic reticulum (ER) function. The figure was created with BioRender.com.
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