Leukocyte motility plays a critical role in inflammatory responses, as it is essential to rapidly recruit innate immune cells to kill pathogens, prevent the spread of microorganisms, trigger inflammation, and repair damage. The classical function of chemokines is to regulate inflammation and drive immune cells through the blood and lymphatic vessels, directing their migration and localization by forming soluble concentration gradients in an autocrine or paracrine manner (Hughes and Nibbs, 2018; Lau et al., 2020). In some contexts, chemokines are also selectively recruited to the cell surface by glycosaminoglycans polysaccharides present within extracellular matrices and at the cell surface which can form fixed concentration gradients and fine-tune the immune response (Paul and Candelario-Jalil, 2021). In NK cells and mast cell precursors, CCR5 binds to locally generated chemokines and inflammatory mediators and causes these innate immune cells to cross the endothelium into peripheral tissues during acute inflammation. Chemokines can regulate immunological responses by guiding regulatory T cell (Treg) migration, and CCR5 may influence the antibody response in the lymph nodes by enhancing the contact of Tregs with B cells and antigen presenting cells (APCs; Maurer and von Stebut, 2004; Khan et al., 2006; Maghazachi, 2010; Griffith et al., 2014). In addition, CCL3/CCR5 was shown to be very effective in augmenting the adhesion of the monocytes to intercellular adhesion molecule-1 during monocyte–endothelial cell interactions, and CCL4/CCR5 can enhance the adhesion of T lymphocytes to vascular cell adhesion molecule 1, which drives immune cell migration from the blood to local tissues across the endothelium (Menten et al., 2002).

Chemokines can induce T cells to differentiate into different subsets and mediate different types of immune responses. Interferon production and macrophage activation are associated with the T helper (Th)1 response; whereas antibody response, B cell assistance, and IL-4 and IL-5 production are associated Th2 response. CCL3, CCL4, and CCL5, which are ligands of CCR5, are chemotactic on Th1 cells, but not on Th2 cells; Th2 cells mainly express CCR2 and CCR4 (Rossi and Zlotnik, 2000; Wong and Fish, 2003). There was a skewed Th2 cytokine profile in mice lacking CCR5, indicating that CCL3/CCR5 and CCL4/CCR5 can influence the immune response by regulating the differentiation of Th to Th1 (Andres et al., 2000; Luther and Cyster, 2001).

Binding of CCR5 to ligands causes the CD8⁺ subset of DC to produce IL-12, which is regarded as a critical step in initiating cell-mediated immunity against intracellular infections (Aliberti et al., 2000). CCR5 is activated when T cells come into contact with APCs and is induced by IL-2 into positive feedback expression on T cells. Simultaneously, CCR5 is recruited to the immunological synapse to reduce T cell responsiveness to other chemotactic substances, through which the stability of T cell-APC interactions is increased and T cell activation is enhanced (Molon et al., 2005). When CD4⁺ T cells interact with DCs, both CD4⁺ T cells and the DC generate CCL3 and CCL4. At the same time, CCR5 is upregulated on naive CD8⁺ T cells entering the lymph node and binds to these chemokines, promoting their migration to CD4⁺ T cell/DC clusters, which finally leads to improved interactions between naive CD8⁺ T cells and DCs licensed by CD4⁺ T helper cells and increased quality and quantity of the CD8⁺ T cell memory response (Del Corno et al., 2001; Griffith et al., 2014). Bystander T cells in the immune system can rapidly respond and secrete cytokines even without antigenic stimulation. CCL5/CCR5 may promote cytokine production and proliferation of bystander T cells, which is important for autoimmunity (Wong and Fish, 2003).

The goal of the host’s reaction to intracellular infections is to eliminate the infected cells as quickly as possible. In addition, it is crucial to remove infected, apoptotic cells from the tissue. Pathogens, activated macrophages, and residual apoptotic cells through proinflammatory proteinases and cytokines cause further tissue damage if the clearance process is disrupted. CCL5-CCR5 interaction can activate MEK-ERK and PI3K-AKT anti-apoptotic signals, which mediate cell growth and survival (Tyner et al., 2005). CCR5 may stimulate T-cell proliferation by triggering STATs (signal transducers and activators of transcription) activation, as chemokine receptors can regulate many transcription factors (López-Cotarelo et al., 2017). By binding to and activating CCR5, CCL5 generated by melanoma tumor cells may trigger the death of tumor-infiltrating T lymphocytes. This process is dependent on the release of cytochrome c into the cytoplasm, rather than on the Fas/Fas ligand. Continued activation of CCR5 by CCL5 following T-cell activation has been shown to cause T-cell death in other studies, indicating that it is a chemokine-dependent late regulation mechanism at an inflammatory site (Wong and Fish, 2003).

Neural progenitor cells express CCR5 and are significantly induced to migrate by CCL5 from activated microglia and astrocytes during human brain development; this migration can be suppressed by antibodies against CCR5 (Park et al., 2009). Mutant CCR5 mice showed fewer and later differentiation of neuronal cells with instant motor deficits, and lacked nociceptive responses, this supports the idea that CCR5 participates in the development of the CNS by inducing neural progenitor cells to migrate to their target destination and promoting neuronal differentiation (Aarum et al., 2003; Tran et al., 2007; Park et al., 2009). CCR5 KO mice have fewer nigral dopaminergic neurons than normal mice, suggesting that CCR5 may play an important role in promoting maturation or development of the nigral dopaminergic system (Park et al., 2009; Choi et al., 2013). Furthermore, the recruitment function of CCR5 promotes monocyte migration along the hippocampal sulcus during brain development and facilitates microglial colonization of the nervous system. Under normal conditions, attracting microglia by chemokines produced by neural progenitor cells may play an essential role in normal brain function, including nutritional support, regulation of neuronal development, and removal of toxic debris (Polazzi and Contestabile, 2002; Ji et al., 2004; Simard et al., 2006; Hahn et al., 2010). Simultaneously, CCR5 ligands from progenitors, microglia, and astrocytes can attract CCR5-expressing dendritic cells, lymphocytes, and monocytes across the immature blood-brain barrier (BBB) into the CNS to inspect the newly generated cells (Cowell et al., 2006; Whitney et al., 2009). CCR5 activation can regulate many transcription factors including cAMP-response-element binding protein (CREB), which participates in a variety of cellular activities and plays an essential role in the CNS, such as neuronal development, neuroprotection, and disease processes (Finkbeiner, 2000; Lonze and Ginty, 2002; Kuipers et al., 2008). These findings may partially explain the function of CCR5 in brain development and neuronal differentiation; however, the implications of these findings remain unclear.

By sensing chemokines in the blood generated by immune cells, area postrema (AP)/nucleus tractus solitarius neurons in the CNS may deliver signals from the active immune system to the CNS. Through voltage-dependent Ca²⁺ channels, chemokine receptors can reduce Ca²⁺ influx so that Ca²⁺-dependent K⁺ currents might be inhibited, thereby regulating neuronal excitability and neurotransmitter release (Oh et al., 2002). However, the activation of presynaptic chemokine receptors on hippocampal neurons can regulate the release of glutamate at these synapses and reduce the frequency by voltage-dependent Ca²⁺ channels; this may produce presynaptic inhibition (Meucci et al., 1998). The current study shows that because of PLC/IP3-induced Ca²⁺ mobilization following G protein activation, CCL5/CCR5 plays a dual role in glutamate transmission: the chemokine inhibits the depolarization-evoked glutamate release, but potentiates the basal release of glutamate (Musante et al., 2008).

C–C chemokine receptor 5 regulates a variety of transcription factors involved in cell survival such as STAT and CREB. Furthermore, because CCR5 mediates crosstalk between glia and neurons, it is critical for neuronal survival in both normal and pathological situations (Choi et al., 2013). Various stimuli may induce the expression of CCR5, such as proinflammatory cytokines TNF-α and INF-γ, lipopolysaccharide (LPS), and hypoxic-ischemic brain injury; these can lead to neuronal death through the release of excitatory amino acids and reactive oxygen species (Hagberg and Mallard, 2005; Kaul et al., 2005; Cowell et al., 2006). During brain aging and neurodegeneration, the function of plasma membrane Ca²⁺-ATPase gradually declines, and a large amount of cytosolic Ca²⁺ released via the CCL5/CCR5 and PLC/IP3 pathways cannot be effectively removed. Inflammatory CCL5 activity and long-lasting Ca²⁺ dyshomeostasis can lead to neuronal apoptosis (Radzik et al., 2019). In addition, chemokines regulate the production of matrix metalloproteinases (MMPs), suggesting that they may contribute to MMP activity-mediated neuronal cell survival and death (Rostène et al., 2007).

As a strong inhibitor of hippocampal and cortical plasticity, CCR5 affects the MAPK/CREB signaling pathway to influence learning and memory. During learning, MAPK and CREB levels are enhanced after CCR5 antagonist use, region-specific viral knockdown, or CCR5 knockout, whereas transgenic mice that overexpress CCR5 in excitatory neurons display learning and memory deficits (Zhou et al., 2016; Merino et al., 2020). The transcription factor CREB in neurons promotes long-term potentiation and enhances synaptic plasticity. Simultaneously, neurons with higher CREB levels are more excitable; consequently, they are more likely to be recruited to participate in the process of learning and memory (Zhou et al., 2009). N-methyl D-aspartate receptor 1 (NMDAR-1) plays an important role in social recognition behavior, as demonstrated by the impaired social recognition of mice with inactive NMDAR-1 receptors. The expression of NMDAR-1 is higher in the brains of CCR5^–/– mice than in those of WT mice; additionally CCR5^–/– mice show a significant improvement in social identification (Kalkonde et al., 2011). Dendritic spine turnover and spine clustering associated with learning and memory depend on NMDAR. In mammals, higher pre-learning spine turnover rates are closely linked to increased levels of learning and memory, which occur during important developmental periods as well as maturity. After CCR5 knockout, increased dendritic spine turnover rates may allow neurons to explore this space more frequently, enhancing connections with appropriate presynaptic neurons and consolidating new synapses through clustering during learning (Frank et al., 2018). CCR5 activation can lead to impaired AMPA-dependent synaptic transmission and significantly reduced excitatory postsynaptic potential, thereby impairing long-term memory and cognitive deficits (Marciniak et al., 2015).

Additionally, astrocytes involved in learning and memory processes can secrete chemokines to mediate synaptic transmission and plasticity after binding to CCR5 via various mechanisms; these including prevention of extrasynaptic neurotransmitter diffusion and removal to modulate synaptic release (De Pitta et al., 2016; Necula et al., 2021).

C–C chemokine receptor 5 participates in the inflammatory response in the CNS not only by mediating immune cell migration but also by affecting the permeability of the BBB and activating microglia (Necula et al., 2021). DCs can acquire essential maturation signals from invading T cells when inflammation occurs around CNS blood arteries. They then operate locally to boost immunological responses or trigger additional waves of autoreactive T cells after traveling to draining lymph nodes (Ambrosini et al., 2005). In the early stages of inflammation, the chemokine CCL5 released from endothelial cells induces resident brain microglia expressing CCR5 to migrate to cerebral vessels, causing microglial cells to infiltrate through the neurovascular unit and express CLDN5. Thus brain microglia initially contact endothelial cells and develop tight junctions to maintain the integrity of BBB. However, prolonged inflammation may cause brain microglia to evolve into a phagocytic phenotype that includes morphological alterations, astrocytic fragment engulfment, and leakage across the BBB. Therefore, CCR5-positive microglia play a dual role in inflammation-induced BBB permeability (Haruwaka et al., 2019). The migration of CCL5-driven peripheral blood mononuclear cells across the BBB is dependent on ligand interactions with CCR1 and CCR5: CCR1 is involved in the arrest, while CCR5 is involved in spreading. These interactions can directly affect the development of certain neuroinflammatory diseases (Ubogu et al., 2006). At the same time, CCR5 activation and Ca²⁺ increase can affect gene expression and microglia activation, which can promote microglial cell activation and proliferation. Therapeutic targeting of CCR5 may decrease BBB leakage, increase neurogenesis stimulated by the excitotoxin kainic acid (KA), and promote migration of bone marrow-derived cells to the brain to become neurons, thereby promoting the repair of nervous system damage (Louboutin and Strayer, 2013).

UsingCCR5 and its ligands, bidirectional interactions between neurons and between neurons and glial cells play a critical role in maintaining normal neuronal activity (Choi et al., 2013). The CCR5/CREB pathway affects plasticity in neurons in a unique way, whereas CCR5 activation in glial cells is intimately linked to elevated Ca²⁺ (Louboutin and Strayer, 2013). Microglia can communicate with immune cells and neurons through a variety of signaling pathways. Microglial cells undergo a complex, multistage activation process, when evidence of brain lesions or nervous system dysfunction is detected, which allows them to migrate to the injury site, phagocytose cells, proliferate, and lead to protective or neurotoxic effects by releasing active substances (Gebicke-Haerter, 2001; Streit, 2002). CCR5 participates in the migration and activation of microglia through Ca²⁺ signaling, which may damage vascular epithelial cells and neurons (Shideman et al., 2006). Furthermore, a GPCR screen showed the role of CCR5 in microglial neurotoxicity suppression; it is activated by RANTES, as a signal mediator between microglia and neurons, and decreases the expression of toxic iNOS and inflammatory cytokines (Gamo et al., 2008). Beyond being a component of the immune response, microglia also can rebuild dendritic spines and synaptic adhesion and transmission after CCR5-mediated migration to ligand-directed chemotactic gradients, which leads to network-level effects (Ekdahl, 2012; Louboutin and Strayer, 2013; Posfai et al., 2019). Astrocytes also respond to a variety of stimuli via CCR5 mediated calcium signals, supporting and modulating particular neuronal networks in different ways after activation by ligands (Ben Haim and Rowitch, 2017). Additionally, astrocytes, which are involved in learning and memory processes, can secrete chemokines to mediate synaptic transmission and plasticity after binding to CCR5 via various mechanisms; these include the prevention of extrasynaptic neurotransmitter diffusion and removal to modulate synaptic release (De Pitta et al., 2016; Adamsky et al., 2018; Allen and Lyons, 2018).