Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

Abstract

Accumulating evidence highlights chemokines as key mediators of the bidirectional crosstalk between neurons and glial cells aimed at preserving brain functioning. The multifaceted role of these immune proteins in the CNS is mirrored by the complexity of the mechanisms underlying its biological function, including biased signaling. Neurons, only in concert with glial cells, are essential players in the modulation of brain homeostatic functions. Yet, attempts to dissect these complex multilevel mechanisms underlying coordination are still lacking. Therefore, the purpose of this review is to summarize the current knowledge about mechanisms underlying chemokine regulation of neuron-glia crosstalk linking molecular, cellular, network, and behavioral levels. Following a brief description of molecular mechanisms by which chemokines interact with their receptors and then summarizing cellular patterns of chemokine expression in the CNS, we next delve into the sequence and mechanisms of chemokine-regulated neuron-glia communication in the context of neuroprotection. We then define the interactions with other neurotransmitters, neuromodulators, and gliotransmitters. Finally, we describe their fine-tuning on the network level and the behavioral relevance of their modulation. We believe that a better understanding of the sequence and nature of events that drive neuro-glial communication holds promise for the development of new treatment strategies that could, in a context- and time-dependent manner, modulate the action of specific chemokines to promote brain repair and reduce the neurological impairment.

Keywords: Central nervous system; Chemokine receptors; Chemokines; Homeostasis.

Fig. 1

Chemokine families. Chemokines are classified into four distinct subclasses: C, CC, CXC, and CX3C according to the number and spacing of their cysteine residues in their N terminus. Cys cysteine residue, X amino acid residue, disulfide bridges are shown as dotted lines

Fig. 2

A schematic diagram provides an overview of the chemokine system’s different cellular/molecular mechanisms in the CNS. a Post-translational modifications exemplified by CX3CL1 transmembrane form cleavage by ADAM10 and ADAM17 proteases into its soluble variant. b The chemokine family redundancy is exemplified by ACKR3. It belongs to the atypical family since it was regarded as unable to induce G-coupled signaling. It binds two chemokines, CXCL11 and CXCL12. Besides the ACKR3 receptor, these two chemokines activate other chemokine receptors, namely CXCR3 and CXCR4, respectively. c Most chemokine receptors can form homo- and hetero-dimers. It is exemplified by the well-known CXCR4–ACKR3 complex. CXCR4 receptor is a ‘classical’ chemokine receptor, which activates G_αq/i signaling pathways, including PKC or (ERK) ½. As an atypical receptor, ACKR3 alone activates β-arrestin-mediated pathways, leading to receptor internalization or scavenging. However, after heterodimerization with CXCR4, it can modify ligand binding properties and receptor signaling as well as intracellular trafficking. d Chemokine ligand bias occurs when specific chemokines could preferentially activate different intracellular pathways, either G-protein or β-arrestin, although binding to the same receptor. It can be due to a specific ligand or receptor, as exemplified here, due to a specific cell. As suggested recently [27], when ACKR3 is activated on neurons, it signals through β-arrestin-mediated pathways, but when it is activated on astrocytes, it recruits β-arrestin-mediated pathways

Fig. 3

Cartoon summarizing a simplified model of coordinated actions of neuron–glia interactions fine-tuned by chosen chemokines and gliotransmitters. a CXCL12 acts on neuronal ADAM17 [68] and releases soluble CX3CL1. b Upon microglial CX3CR1 activation, CXCL16 is secreted from microglia ([38]), and c acts on astrocytes by inducing the additional release of CCL2. Notably, other soluble factors that mediate CXCL16-dependent neuroprotection cannot be excluded since blocking CCL2 activity dramatically reduces, but did not fully abolish, its ability to preserve neurons ([38]). d CX3CL1 acts on microglia and releases the adenosine that exerted their effects on astrocytes by binding to A₁R, and e consequently induces the up-regulation of the astrocytic GLT-1 transporter ([78]). f CXCL12 is produced by microglia and acts, for example, on CXCR4 on neurons and astrocytes [30]. g TNFα leads to remyelination [79]

Fig. 4

A simplified schematic diagram that provides an overview of the chemokine system’s synaptic/network mechanisms in the CNS exemplified by the CX3CL1/CX3CR1 axis. a, b In CA1, CX3CL1 reduces glutamatergic synaptic transmission and amplitude of LTP by indirect, microglia action. Briefly, CX3CL1 activates CX3CR1 on microglia, and thus, these cells secrete adenosine. Then, adenosine, via A₃R receptors on postsynaptic neurons, dephosphorylates the AMPA subunit, thus leading to reduced glutamatergic transmission and reduction in the LTP. Based on c, chemokines regulate adult neurogenesis. Specifically, CX3CL1 may play a role in hippocampal neurogenesis by inhibiting the release of IL-1β from microglial cell types. d CX3CL1 is also documented to modulate coherence of hippocampal–prefrontal cortex connection. Schematic based on results of [120]