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. 2021 Jun 12;42(7):2147–2156. doi: 10.1007/s10571-021-01115-1

The CXCL12/CXCR4/ACKR3 Response Axis in Chronic Neurodegenerative Disorders of the Central Nervous System: Therapeutic Target and Biomarker

Yudie Yan 1, Jingtong Su 2, Zhen Zhang 1,✉
PMCID: PMC11421623  PMID: 34117967

Abstract

There has been an increase in the incidence of chronic neurodegenerative disorders of the central nervous system, including Alzheimer’s and Parkinson’s diseases, over the recent years mostly due to the rise in the number of elderly individuals. In addition, various neurodegenerative disorders are related to imbalances in the CXCL12/CXCR4/ACKR3 response axis. Notably, the CXC Chemokine Ligand 12 (CXCL12) is essential for the development of the central nervous system. Moreover, the expression and distribution of CXCL12 and its receptors are associated with the aggravation or alleviation of symptoms of neurodegenerative disorders. Therefore, the current review sought to highlight the specific functions of CXCL12 and its receptors in various neurodegenerative disorders, in order to provide new insights for future research.

Keywords: ACKR3, CXCL12, CXCR4, Neurodegenerative disorders, Central nervous system

Introduction

According to the World Health Organization (WHO), there has been a dramatic increase the number of elderly individuals across the globe. In addition, the population of individuals aged 60 years or older is expected to be 2 billion by 2050. By this time (2050), China will be home to about 120 million elderly in individuals and 434 million more will be distributed across the globe (https://www.who.int/). However, the rise in the aging population has led to a corresponding increase in the incidence of neurodegenerative disorders which not only affect the health of elderly individuals but also their quality of life. Additionally, more research focus has been directed to neurodegenerative disorders over the recent years.

Neurodegenerative disorders are caused by the loss of neurons and (or) the myelin sheath. The diseases get worse with age and finally result in dysfunction of consciousness and (or) behavior, which becomes a considerable burden for both patients and the society (Chen et al. 2020).

Additionally, neurodegenerative disorders can be divided into two types, namely, acute neurodegenerative disorders and chronic neurodegenerative disorders. The acute neurodegenerative disorders mainly include Cerebral Ischemia (CI), Brain Injury (BI), and epilepsy. On the other hand, the chronic neurodegenerative disorders include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), different types of Spinocerebellar Ataxia (SCA), and Pick’s Disease. The present review mainly focuses on the chronic neurodegenerative disorders of the Central Nervous System (CNS).

Notably, most neurodegenerative disorders have common clinical features, including cognitive impairment, motor system defects, and sleep disorders. The diseases also have common molecular mechanisms, including signaling pathways, protein aggregation, and diffusion from one region to another (Gan et al. 2018).

Chemokines are small cytokines or signal proteins secreted by cells, which play a role in inducing directional chemotaxis of the microglia and other immune cells in many physiological and pathological processes. In addition, chemokines can be divided into four subfamilies, namely, CXC, CC, C, and CX3C. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors (or chemokine receptors) that are selectively expressed on the surface of target cells (Gilchrist 2020).

Moreover, chemokines can regulate the release and conduction of neurotransmitters as well as the growth and development of neurons (Liu et al. 2019). Some chemokines also play an important role in cell differentiation and adult hippocampal neurogenesis and may maintain learning and memory processes, particularly long-term memory (Abe et al. 2018; Trousse et al. 2019). Furthermore, there are many receptors for the Nerve Growth Factor (NGF) in chemokines family, and NGF receptors also exist in glial cells (Capsoni et al. 2017).

Notably, an imbalance of chemokines and their receptors creates an environment for tumor growth and metastasis in some disorders (Richmond 2002; Sarvaiya et al. 2013). Additionally, expression of the chemokine ligand, CCL2 (also known as the Monocyte Chemoattractant Protein-1, MCP-1) was shown to be up-regulated during the progression of the prion disease (Felton et al. 2005).

Moreover, the CXC Chemokine Ligand 12 (CXCL12) was first identified in the bone marrow (Li and Ransohoff 2008). It is a small cytokine molecule, belonging to the chemokine protein family and is also known as the Stromal cell-derived Factor-1 (SDF-1). Notably, there are two forms of CXCL12: SDF-1α/CXCL12a and SDF-1β/CXCL12b (De La Luz Sierra et al. 2004). SDF-1α and SDF-1β have the same amino acid sequence, but there are four other amino acids at the carboxyl end of SDF-1β (De La Luz Sierra et al. 2004). However, the significance of the two splicing forms of SDF-1 remains unclear (De La Luz Sierra et al. 2004). In addition, CXCL12 and its receptors, including CXCR4, CXCR7, and GAG, are widely expressed in the central nervous system. Furthermore, changes in their expression are affected by microRNA (miRNA) and transcription factors (Sierro et al. 2007), which play important roles in various pathological conditions of the brain, including neurodegenerative disorders such as AD, ALS, and autoimmune Multiple Sclerosis (MS) (Petković et al. 2013; Bonham et al. 2018; Janssens et al. 2018).

Therefore, it is important to find biomarkers and therapeutic targets for neurodegenerative disorders by highlighting the regulatory mechanism involving CXCL12, CXCR4, CXCR7, and other factors. Consequently, the present review aimed to elucidate the role of CXCL12 and its receptors in neurodegenerative disorders in order to provide a reference point for future research. The specific functions of CXCL12 and its receptors as well as the changes and specific effects of their expression in neurodegenerative disorders are also discussed in this review. Table 1 shows the expression of cytokines and their role in neurodegenerative disorders.

Table 1.

The expression of chemokines and their role in neurodegenerative disorders

Official name Synonyms Neurodegenerative disorders Expression Effect References
CXCL12 SDF-1 Progressive supranuclear palsy (PSP) Significant disorder (Bonham et al. 2018)
Parkinson disease (PD) Significant disorder/up-regulation (Bagheri et al. 2018; Bonham et al. 2018)
Frontotemporal dementia (FTD) No significant abnormality Protective chemokine (Bonham et al. 2018, Andrés-Benito et al. 2020)
Alzheimer’s disease (AD) Down-regulation Protective chemokine (Laske et al. 2008; Wang et al. 2017; Luke et al. 2018)
Atrophic lateral sclerosis (ALS) Up-regulation Stable or increase in cerebrospinal fluid (Bonham et al. 2018)
Multiple sclerosis (MS) Disorder/up-regulation (Calderon et al. 2006; McCandless et al. 2008; Bonham et al. 2018; Magliozzi et al. 2018,2019)
CXCR4 Progressive supranuclear palsy (PSP) Up-regulation Slight correlation with the activation of microglia (Bonham et al. 2018)
Parkinson’s disease (PD) Up-regulation No correlation with the activation of microglia (Bonham et al. 2018)
Frontotemporal dementia (FTD) Up-regulation Significantly correlated with the activation of microglia (Janssens et al. 2018)
Atrophic lateral sclerosis (ALS) Up-regulation Inhibition of CXCL12-CXCR4 or CXCL12-CXCR7 axis can delay or prevent the progression of amyotrophic lateral sclerosis (Rabinovich-Nikitin et al. 2016; Janssens et al. 2018, Andrés-Benito et al. 2020)
CXCR7 ACKR3 Atrophic lateral sclerosis (ALS) Disorder Expressed in reactive astrocytes in late ALS (Andrés-Benito et al. 2020)
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CXCL12 and its Receptors in the Central Nervous System

The known CXCL12 receptors include CXCR4 and CXCR7 which are widely expressed in the central nervous system and play important roles in various physiological and pathological conditions (Petković et al. 2013; Janssens et al. 2018). In addition, Glycosaminoglycan (GAG) can act as a functional chemokine signal auxiliary receptor, resulting in the formation of GAG-chemokine-chemokine receptor ternary complexes (Handel et al. 2005).

The CXC Chemokine Ligand 12 (CXCL12)/Stromal Cell-Derived Factor 1 (SDF-1)

CXCL12 is a small cytokine molecule, belonging to the chemokine protein family and is also referred to as the Stromal cell-derived Factor-1 (SDF-1) (Li and Ransohoff 2008). It has two splicing forms, namely, SDF-1α/CXCL12a and SDF-1β/CXCL12b (De La Luz Sierra et al. 2004). However, the significance of the two splicing forms of CXCL12 remains largely unclear (De La Luz Sierra et al. 2004). Moreover, CXCL12 acts synergistically with other CXC and CC chemokines in attracting B and T cells, monocytes, dendritic cells, microglia, and progenitor cells (Gouwy et al. 2014). These autoimmune cells in turn play an important role in regulating neuroinflammation, thus aggravating or alleviating neurodegenerative disorders. Additionally, the behavior of microglia is highly dependent on chemokines and cytokines and the response may change based on the form of stimulation (Hanisch 2002). Microglia can also receive chemokine signals as a part of communication with astrocytes, neurons, and endothelial cells (Hanisch 2002). Furthermore, microglia can provide nutrition to neurons, promoting the differentiation of oligodendrocytes and regulating synaptic plasticity (Aguzzi and Zhu 2017; Di Benedetto 2019; McQuade and Blurton-Jones 2019).

Previous research also identified CXCL12 in the Cerebrospinal Fluid (CSF) of patients with inflammatory neurological diseases. In addition, the CXC chemokine receptor 4 (CXCR4) is one of the receptors for CXCL12. It was also shown that there was an increase in the levels of CXCL12 and CXCR4 in microglia pretreated with a Lipopolysaccharide (LPS) (Gao et al. 2017). Moreover, there was an increase in the expression of CXCR4 in the mouse microglia BV-2 cell line, following the secretion of CXCL12 (Li et al. 2019). These results therefore suggest that the chemokine pathway may play an important role in glial response and neuroinflammation through the CXCL12/CXCR4 and CXCL12 / CXCR7 pathways.

Interestingly, CXCL12-mediated attraction of microglia has different results in different neurodegenerative disorders (Janssens et al. 2018). For instance, Bonham et al. showed that the expression of CXCL12 was significantly impaired in PSP and PD, while there was no significant abnormality in FTD (Bonham et al. 2018). The detailed role of CXCL12 in various neurodegenerative disorders will be elaborated in the next section of this review.

Moreover, CXCL12 is involved in the biological behavior of neural precursor cells in the nervous system. It was also reported that normal neurogenesis and proper homing of neural precursor cells to the neuronal origin in adult CNS require the activation of CXCR4 by CXCL12 (Williams et al. 2014a, b). In addition, CXCL12 regulates the migration of neural precursor cells and can also act as a signal to guide axon growth (Li and Ransohoff 2008). Existing evidence also shows that defects in the proliferation of precursor cells in the dentate gyrus are linked to decreased expression of CXCR4/CXCL12 and knockout of CXCL12 or CXCR4 can lead to significant changes in the proliferation, migration, and differentiation of neural precursor cells (Trousse et al. 2019).

Furthermore, CXCL12 mediates the repair of damaged nerve tissue. Notably, CXCL12 can promote the recruitment of precursor cells in lesion sites and regeneration of the nervous system following different injuries. After traumatic brain injury, CXCL12 promotes the proliferation of glial cells and migration of neuroblastoma (Zhang et al. 2018, Mao et al. 2020). A previous report also showed that CXCL12 is directly involved in the activity of the Nerve Growth Factor (NGF), including the rescue of synaptic plasticity, memory dysfunction, and neurodegeneration in 5xFAD mice and significantly reduced the deposition of amyloid-β. Moreover, the study proposed that these actions were mediated by glial cells (Capsoni et al. 2017).

It is also noteworthy that microglia may play two opposite roles in different diseases of the central nervous system. On one hand, microglia are beneficial to the development of the CNS and alleviation of diseases. For example, microglia promote the formation of learning-dependent synapses through Brain-derived Neurotrophic Factor (BDNF) signaling, which plays an important role in learning and memory (Parkhurst et al. 2013). On the other hand, although neuroinflammation is a defense mechanism that initially protects the brain by removing or inhibiting a variety of pathogens, persistent inflammation involving microglia and astrocytes can aggravate or lead to neurodegenerative disorders (Kempuraj et al. 2016).

Activated microglia secrete IL-1α, tumor necrosis factor-α and C1q which induce type A1 reactive astrocytes, leading to the loss of neurotrophic function and neuronal death (Aguzzi and Zhu 2017). Additionally, activation of microglia due to aging and chronic stress showed the morphology of malnutrition and excessive inflammatory response (Niraula et al. 2017). Over activation of microglia also results in migration, clearance, and anti-inflammatory state-related dysfunction, leading to increased susceptibility to neurodegeneration (Triviño and von Bernhardi 2021).

CXCL12 also maintains normal physiological function of the CNS. In addition, it helps in maintaining the regulatory effect of the cAMP Response Element Binding protein (CREB) on brain plasticity and excitability of memory formation (Trousse et al. 2019). Moreover, a decrease in the expression of CXCL12 can interfere with normal neuronal signal transmission, hence having a negative impact on memory processing. Knockdown of CXCL12 can also lead to the activation of microglia. Notably, animals in which CXCL12 was knocked down showed obvious behavioral and learning defects, which was related to the damage of hippocampal neurons. Interestingly, increased expression of CXCL12 and CXCR4 can reduce epileptic seizures and cognitive impairment (Trousse et al. 2019).

In addition, CXCL12 is associated with the integrity of the Blood–Brain Barrier (BBB). It is also noteworthy that abnormal expression of CXCL12 is almost involved in all kinds of neurodegenerative disorders because destruction of the BBB occurs during the pathogenesis of various neurodegenerative disorders, and infectious and autoimmune diseases (Panganiban et al. 2020).

In general, CXCL12 has numerous functions in the central nervous system. Notably, CXCL12 can regulate the behavior of autoimmune cells and neural precursor cells, mediate the repair of damaged nerve tissue, maintain the normal physiological function of the central nervous system, and is associated with the integrity of the blood–brain barrier. More functions of CXCL12 may be uncovered in future.

The Receptors of CXCL12

The CXC Chemokine Receptor 4 (CXCR4)

CXCR4 is a chemokine receptor protein that plays an important regulatory role in immune reaction and nerve development (Kokovay et al. 2010). A previous study showed that when the CXCR4 signal was inhibited by drugs, the memory of experimental animals was affected (Trousse et al. 2019). It was also reported that up-regulation of CXCR4 expression during age-related nerve degeneration was related to the inflammatory mechanism in Tau-P301L mice (Kokovay et al. 2010). Additionally, Bonham et al. showed that a mutation near chemokine CXCR4 increased the risk of PSP and PD (Bonham et al. 2018).

In addition, CXCR4 can regulate the development of T and B lymphocytes, the generation of memory T cells, the maintenance of mature lymphocytes, therefore enhancing the inflammatory response (Li and Ransohoff 2008). CXCR4 also promotes the activation of microglia but this role does not exist in all neurodegenerative disorders (Bonham et al. 2018). For instance, the up-regulation of CXCR4 in FTD is significantly correlated with the activation of microglia. However, there was only a slight correlation in PSP and no correlation in PD (McQuade et al. 2020). Changes in the expression of CXCR4 were also reported in various abnormal microglia. Moreover, the expression of CXCR4 was up-regulated in Disease-Associated Microglia (DAM) (Keren-Shaul et al. 2017; Krasemann et al. 2017) and plaque-related human microglia (Hasselmann et al. 2019). A previous study also reported a decrease in CXCR4 in immortalized Glial cell-restricted Precursors (GRIPs) derived from the E11.5 neural tube of wild-type and SOD1 (G93A) mutant mice. The SOD1 (G93A) GRIPs could not respond to SDF-1α to activate the ERK1/2 enzyme and transcription factor CREB, hence affecting the transduction of CXCR4 signals (Luo et al. 2007).

Furthermore, CXCR4 is strongly associated with microglia-related genes, including CXCL12, toll-like receptor-2 (TLR2), and chemokine receptor CCR5. In addition, the downstream response of CXCR4 is related to Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) signal transduction, which mediates the migration of microglia. Microglia in which TREM2 was knocked out were also shown to be deficient in CXCR4 which is required for migration (McQuade et al. 2020).

According to previous studies, the downregulation of CXCL12 chemokines in mice is accompanied by a decrease in CXCR4 expression. This leads to the activation of glial cells and affects the regulation of immediate-early gene expression as well as cell proliferation in the dentate gyrus, hence affecting the learning ability of mice (Trousse et al. 2019). Additionally, use of AMD3100 to block CXCR4 signal transduction is sufficient to prevent microglia from migrating to neurons and astrocytes producing the β-amyloid protein. This indicates that CXCR4 signal transduction may provide potentially useful therapeutic targets that enable microglia to clear amyloid plaques and degenerating neurons (McQuade et al. 2020).

The Atypical Chemokine Receptor 3 (ACKR3)/CXC Chemokine Receptor 7 (CXCR7)

ACKR3 is also known as CXCR7 and can interact with the CXC Chemokine Ligand 11 (CXCL11, also known as the Interferon-induced T cell α Chemokine [ITAC]) or CXCL12 (also known as SDF-1). After the activation of CXCR7, the β-inhibitor protein can be recruited to the cell membrane. Given that this process is not achieved by initiating G protein signal transduction but through the β-arrestin pathway, the receptor is referred to as the “atypical chemokine receptor” (Rajagopal et al. 2010).

In addition, CXCR7 maintains the polarity of CXCL12 in the blood–brain barrier (Williams et al. 2014a, b). CXCR7 also binds to CXCL11 and CXCL12 with high affinity and removes them through internalization (Boldajipour et al. 2008). Moreover, experimental evidence in mesenchymal stem cells shows that CXCR7 not only regulates the expression of CXCL12 but also induces the differentiation of mesenchymal stem cells into alveolar cells (Yuan et al. 2018).

It was also reported that downregulation of CXCR7 led to a decrease in the levels of c-Fos and Creb1. Additionally, downregulation of CXCR7 impaired the maturation of dentate gyrus cells and the CXCL12-CXCR4 signaling pathway, hence interfering with the ability to learn (Sierro et al. 2007). Moreover, knockout of CXCR7 causes postnatal death and cardiac defects in mice (Sierro et al. 2007). A previous study also showed that knockdown of CXCR7 and CXCL12 results in learning and memory deficits (Trousse et al. 2019).

Furthermore, CXCR7 is related to the differentiation of cells in the central nervous system. It was also reported previously that CXCR7 is related to the differentiation of oligodendrocytes in the central nervous system and controls the migration of several neurons during embryonic development (Williams et al. 2014a, b). Additionally, animals in which CXCR7 was knocked down showed mild learning disabilities and normal neurogenesis but failure in the differentiation of newborn neurons in the hippocampus (Trousse et al. 2019).

Glycosaminoglycan (GAG)

Glycosaminoglycan (GAG), such as heparin and heparan sulfate, is a complex linear polysaccharide which together with fibrin constitutes the extracellular matrix of all vertebrates (Janssens et al. 2018). Additionally, the interaction between GAG and its target proteins in the extracellular matrix depends on their sulfation and influencing processes, such as tissue hemostasis, lipid transport, absorption, cell growth, cell migration, and tissue repair (Köhling et al. 2019). GAG can also act as a functional chemokine signal auxiliary receptor during the formation of GAG-chemokine-chemokine receptor ternary complexes (Handel et al. 2005). Moreover, chemokines can bind to GAG produced naturally by heparin through various molecular interactions (Spiller et al. 2019). The binding of chemokines to GAG also depends on the ionic force between the negatively charged chain of GAG and the residue cluster of chemokines (Handel et al. 2005). Notably, GAG–chemokine interaction plays a key role in establishing the extracellular gradient (Handel et al. 2005). In addition, the interaction with GAG ensures the correct presentation of chemokines in tissues and endothelial cells. It also activates and attracts target cells by forming a chemotaxis gradient (Handel et al. 2005).

On the other hand, SDF-1/CXCL12 belongs to the chemokine family and exerts its biological activity by activating G protein-coupled receptors. It also binds to soluble GAG carried by membrane protein polysaccharides (Rossi and Zlotnik 2000). Additionally, several positively charged amino acids are usually located in close proximity, in the tertiary structure of CXCL12 and mediate the interaction with negatively charged GAG polymers (Janssens et al. 2017). Existing evidence also suggests that the binding of GAG to chemokines and regulation of the biological activity of SDF-1/CXCL12 are mainly related to the presence of sulfate (Friand et al. 2009). Moreover, the effect of GAG on SDF-1/CXCL12-mediated chemotaxis of hepatocellular carcinoma cells may depend on the decrease in the expression of heparinase (Friand et al. 2009).

Furthermore, it was reported that GAG is involved in CXCL12/SDF-1-induced proliferation, migration, and invasion of human hepatocellular carcinoma cells through CXCR4 (Rueda et al. 2012). In mice expressing CXCR4 and CXCL12 but lacking the GAG binding motif, the increase in the number of progenitor cells and the decrease in the number of invasive cells in circulation proved that the correct binding of GAG and receptor activation were necessary for the activity of CXCL12 (Rueda et al. 2012).

CXCL12 and Neurodegenerative Disorders

Alzheimer’s Disease (AD)

Alzheimer’s disease is the most common form of dementia and its main pathological features include extracellular accumulation of the amyloid β protein (Aβ), hyperphosphorylation of the tau protein, and neurofibrillary tangles (Baufeld et al. 2018). In addition, many cellular mechanisms of AD, including the insulin signaling pathway, the MAPK signaling pathway, and the extracellular signal regulated kinase pathway, have been well studied. However, the failure rate of research and development of drugs against AD is much higher than that in other fields and the drugs that are introduced for clinical use are finally terminated or suspended. Therefore, it is necessary to find new therapeutic targets.

According to previous research, CXCL12 is a protective chemokine in AD (Janssens et al. 2018). Additionally, there was a significant decrease in CXCL12 chemokine signaling in AD patients and transgenic AD mice with impaired memory function (Laske et al. 2008; Wang et al. 2017; Luke et al. 2018). Intraventricular injection of CXCL12 also reduced deposition of the amyloid protein and promoted phagocytosis of the amyloid protein by microglia (Wang et al. 2012). Moreover, there was a significant change in the expression of CXCR4 and functionally related genes in regions where Neurofibrillary Tangles (NFT) accumulated most in the brain of mice (Bonham et al. 2018). In addition, Laske et al. reported that the levels of CXCL12 and CXCR4 in patients with AD were lower than those in non-dementia controls, supporting the role of chemokines in memory function (Laske et al. 2008). Trousse et al. also proved the role of CXCL12 and its receptors in learning and memory. This highlighted a potentially new way related to the memory process and may be a new target for the management of learning and memory-related diseases, including AD (Trousse et al. 2019). Furthermore, CXCL12 regulates the behavior of microglia. Notably, microglia and neuroinflammation are strongly associated with genetics and neuropathology in delayed AD (Jansen et al. 2019).

Genetic susceptibility and environmental factors are two important factors in AD. Additionally, herpesvirus infection has long been considered to be associated with susceptibility to AD (Wang et al. 2020). CXCL12 and its receptors are also associated with several types of viral infections. Moreover, the Herpesvirus-8 (HHV-8) genome contains a chemokine-like gene, the viral Macrophage Inflammatory Protein-II (vMIP-II), which is an effective antagonist of CXCR4 (Kledal et al. 1997).

Parkinson’s Disease (PD)

Parkinson’s disease is one of the most common neurodegenerative disorders. Its main pathological features include the degeneration of dopaminergic neurons in Substantia Nigra (SN) and formation of Louis bodies containing α-synuclein aggregates. Studies have shown that the microglia in substantia nigra may induce inflammation, which may be one of the reasons behind α-synuclein-mediated toxicity (Zella et al. 2019). In addition, the accumulation of reactive microglia was reported in autopsy brain samples from patients with PD (Deleidi and Gasser 2013). It was also reported that activated microglia gather in the brain of PD patients and release cytokines to promote disease progression (Tansey and Goldberg 2010). Moreover, α-synuclein activates microglia to release pro-inflammatory and chemotactic cytokines and induces dopaminergic neurodegeneration (Haenseler et al. 2017).

Additionally, Bagheri et al. assessed the expression of CXCL12 and CXCR4 in the peripheral blood of 30 patients with PD and 40 controls. Their findings showed that the level of CXCL12 in the serum of patients with PD and the expression of CXCR4 in peripheral blood mononuclear cells were significantly higher than those in the control group (Bagheri et al. 2018). It is was therefore suggested that the presence of CXCL12 or CXCR4 in peripheral blood may be a biomarker of PD. Moreover, Li et al. showed that there was an increase in the expression of CXCL12 in the SN tissues of PD patients and A53T mice (α-synuclein mutant mice) (Li et al. 2019). It was also reported that α-Synuclein can promote the secretion of CXCL12 by microglia through the TLR4/IκB-α/NF-κB pathway. Furthermore, inhibition of TLR4 can significantly reduce the expression of CXCL12 (Li et al. 2019). CXCL12 also participates in the migration of microglia, induced by the binding of α-Synuclein to CXCR4. In addition, FAK/Src mediates the directional migration of microglia to the substantia nigra after triggered by CXCL12 (Li et al. 2019).

Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis is a kind of motor neuron diseases. The main feature of the disease is progressive and irreversible loss of motor neurons, which usually leads to muscle atrophy and death within 5 years after the onset of ALS (Hortobágyi and Cairns 2017). Notably, a previous study showed 51 differentially expressed proteins in the CSF of patients with sporadic ALS, through Liquid Chromatography–tandem Mass Spectrometry (LC–MS/MS). Out of the identified proteins, CXCL12 was the most valuable candidate biomarker (Andrés-Benito et al. 2020).

Additionally, CXCL12 was expressed in the motor neurons in both normal and ALS patients and expressed in a few glial cells in late ALS (Andrés-Benito et al. 2020). In ALS, activated microglia produce pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6 and then produce Reactive Oxygen Species (ROS) and Nitric Oxide (NO) (Drechsel et al. 2012). A previous study also reported that CXCR4 was expressed in oligodendrocyte-like cells and the enlargement of axons of motor neurons in ALS (Andrés-Benito et al. 2020). Additionally, by treatment with the CXCR4 inhibitor, AMD3100 in ALS mice model led to a decrease in the microglia inflammatory markers, reduced the permeability of the blood–brain barrier, and improved the survival rate (Rabinovich-Nikitin et al. 2016). Moreover, Povedano et al. reported that CXCR7 was expressed in the motor neurons of normal people but expressed in reactive astrocytes in people with late ALS (Andrés-Benito et al. 2020). Furthermore, the CXCL12/CXCR4/CXCR7 axis may play a complex role in inflammation, oligodendrocyte signal transduction, astrocyte signal transduction, neuronal protection, and axon protection in ALS (Andrés-Benito, Povedano et al. 2020). For instance, it was shown that inhibition of the CXCL12-CXCR4 or CXCL12-CXCR7 axis can delay or prevent the progression of ALS (Rabinovich-Nikitin et al. 2016; Janssens et al. 2018).

Multiple Sclerosis (MS)

Multiple sclerosis can lead to neurodegeneration although it is mainly considered to be an autoimmune disease, characterized by inflammatory demyelination of the white matter in the central nervous system, often involving the periventricular white matter, optic nerves, and the brainstem (Khorramdelazad et al. 2016). According to previous research, the level of CXCL12 is elevated in the cerebrospinal fluid of patients with MS and the level can remain stable or increase with the progression of the disease (Magliozzi et al. 2018; Magliozzi et al. 2019, Andrés-Benito et al. 2020). Additionally, CXCL12 is expressed in astrocytes in active MS while it is almost only expressed in endothelial cells in healthy brain tissues (McCandless et al. 2008). Eugenin et al. also reported that there was an increase in the level of CXCL12 in vitro cultured astrocytes after being stimulated with the soluble myelin basic protein or IL-1β and this was related to the development of MS (Calderon et al. 2006).

The severity of MS is associated with the redistribution of CXCL12 from the outside of the Blood–brain Barrier (BBB) to the lumen (McCandless et al. 2008). In addition, CXCR7 internalizes CXCL12 in the lateral basal ganglia, disrupting the polarity of monocytes invading the central nervous system. According to a previous study, CXCL12 was expressed outside the base of the BBB, in healthy brain tissues (McCandless et al. 2008). Additionally, CXCL12 is redistributed from the parenchyma to the endothelial side of the lumen, in active MS lesions (McCandless et al. 2008). Notably, treatment of Experimental Autoimmune Encephalomyelitis (EAE) mice with the small molecule CXCR7 inhibitor, CCX771, reduced the clinical severity of EAE, reduced the inflow of white blood cells, lead to a decrease in demyelination, and increased CXCR4-mediated myelin formation (Cruz-Orengo et al. 2011; Williams et al. 2014a, b).

Treatment of MS usually involves the use of immunosuppressants such as corticosteroids to suppress neuroinflammation. It should however be noted that targeting the CXCL12/CXCR4 axis is unfavorable for the treatment of multiple sclerosis due to the neuroprotective effect of CXCL12 as well as the decrease in the levels of effective CXCL12 or the aggravation of EAE after inhibition of CXCR4 (Janssens et al. 2018).

Other Neurodegenerative Disorders

A previous study showed that the expression of CXCL12 was significantly impaired in PSP and PD although there was no marked abnormality in FTD (Bonham et al. 2018). In addition, the up-regulation of CXCR4 is significantly correlated with the activation of microglia in FTD. Nonetheless, there was only a slight correlation between CXCR4 and activation of microglia in PSP and no association in PD (McQuade et al. 2020).

In addition to the neurodegenerative disorders mentioned above, other chronic neurodegenerative disorders include the Huntington’s Disease (HD), different types of Spinocerebellar Ataxia (SCA), Progressive Supranuclear Palsy (PSP), and Frontotemporal Dementia (FTD). However, little information exists on the expression and roles of CXCL12 in these neurodegenerative disorders. More research is therefore needed to highlight the role of CXCL12 in these diseases.

Conclusion and Perspective for Future Development

With the increase in life expectancy, there is a significant increase in the impact of neurodegenerative disorders on global social economy. However, the pathological mechanism of neurodegenerative disorders has not been fully elucidated. Notably, abnormal protein kinetics, oxidative stress caused by reactive oxygen species, mitochondrial dysfunction, DNA damage, and neuroinflammatory processes are considered to be the common pathophysiological mechanisms underlying neurodegenerative disorders. In addition, studies have shown that neuroinflammation occurs in many neurodegenerative disorders and it is closely related to the microglia and chemokines. A number of studies also proposed that neurodegenerative disorders may have a common molecular basis. Additionally, abnormal signaling of the microglia may lead to neurodegeneration and immune dysfunction in patients with neurodegenerative disorders.

Chemokines belong to a rapidly expanding family of cytokines, whose main function is to control the correct location of cells in tissues and the recruitment of leukocytes to inflammatory sites. Therefore, understanding these important inflammatory cytokines can help in uncovering the role of inflammation in the progression of neurodegenerative disorders. So far, some chemokines have been identified in the resident cells of the central nervous system. Moreover, the expression of chemokines and their receptors in the central nervous system varies under different physiological and pathological conditions.

This review summarized the regulatory factors and functions of CXCL12 and its receptors, which are abundantly expressed in the central nervous system. However, different studies reported different levels of CXCL12 expression and opposite results were even obtained in the same disease. This phenomenon may be due to the distinct levels of CXCL12 expression in different animal tissues. Therefore, the expression of CXCL12 in different animal tissues, such as peripheral blood, substantia nigra, and the dentate gyrus needs to be verified further. CXCL12 often plays a role in disease progression or remission by activating the microglia. Additionally, the activation of microglia has different results in different neurodegenerative disorders, suggesting that its specific mechanism needs to be explored further. In addition to CXCL12 and its receptors, some microRNAs, long non-coding RNAs, and circular RNA that can regulate the expression and distribution of CXCL12 or other chemokines need to be studied as well.

Moreover, it is noteworthy that the existence of multiple splicing variants of CXCR4 and CXCL12 increases the complexity of their functions and post-translational modifications also have potential roles. Furthermore, microglia can be divided into the M1 and M2 phenotypes according to their activation status, but their functions may vary with the stage and severity of neurodegenerative disorders and cannot simply be divided into two types. In addition, HD, different types of SCA, PSP, and FTD are also neurodegenerative disorders. However, the role of CXCL12 and its receptors in the occurrence and development of these neurodegenerative disorders needs to be studied further.

In conclusion, there are still numerous gaps on the role of CXCL12 and other chemokines in neurodegenerative disorders. Additionally, drugs targeting CXCL12 and other chemokines have been proven to reduce the symptoms of neurodegenerative disorders. Therefore, studying the role of chemokines in neurophysiology and their involvement in neuropathological conditions can uncover new therapeutic approaches and biomarkers for the early diagnosis of neurodegenerative disorders.

Abbreviations

PSP

Progressive supranuclear palsy

PD

Parkinson disease

FTD

Frontotemporal dementia

AD

Alzheimer’s disease

MS

Multiple sclerosis

SDF-1

Stromal cell-derived factor 1

CXCL12

CXC chemokine ligand 12

CXCR4

CXC chemokine receptor 4

ACKR3

Atypical chemokine receptor 3

CXCR7

CXC chemokine receptor 7

GAG

Glycosaminoglycan

Author Contributions

YY conceived the study and wrote the manuscript; JS contributed to manuscript preparation and data analysis and interpretation; ZZ revised the work critically for important intellectual content and approved the version to be published.

Funding

This research was supported by the Natural Science Foundation of Liaoning Province, China (2019-ZD-0772) and the National Natural Science Foundation of China (Grant Nos. 81471809; 81971639).

Data Availability

All data generated or analyzed during this study are included in this published article.

Declarations

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