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.

IFN-γ deficiency in the rostral ventrolateral medulla contributes to stress-induced hypertension by impairing microglial synaptic engulfment

“…Studies have suggested that IFN-g induced the production of CCL2 [21,35]. CCL2 downregulation is involved in abnormal microglia-mediated neuronal synaptic engulfment, causing increased neuronal excitability [21,22]. In this study, the expression levels of IFN-g and CCL2 were decreased in the RVLM of SIH rats.…”

“…IFN-g mediates the activation of the JAK1/2 pathway, which leads to the high expression level of neuronal CCL2 [21]. Abnormal CCL2 expression is related to the microglial synaptic engulfment involved in neuronal activity [22,23]. Neuronal CCL2 knockout could impair microglial synaptic engulfment, thereby affecting neuronal function [21].…”

Neuro-immune modulation of cholinergic signaling in an addiction vulnerability trait

“…In brain, chemokines are primarily secreted from microglia and neurons, and receptors for chemokines are expressed by neurons and all types of glial cells. Brain chemokines can influence synaptic mechanisms in part via astrocyte-synapse interactions (Biber et al, 2002; Bezzi et al, 2001; Adler and Rogers, 2005; Melik-Parsadaniantz and Rostene, 2008; Sowa and Tokarski, 2021). Thus, elevated of levels of brain chemokines may not necessarily indicate an active neuro-immune response but, independent from their chemotactic capacity, may serve as a neuro-modulatory system that is neuronally regulated and in turn influences neuronal communication and behavior (e.g., Vitkovic et al, 2000; Prieto and Cotman, 2017; Vezzani and Viviani, 2015; Bourgognon and Cavanagh, 2020; Donzis and Tronson, 2014; Davis and Krueger, 2012).…”

Impact of SARS-CoV-2 on Host Factors Involved in Mental Disorders

“…However, it is also capable of activating glial cells of the CNS, releasing several inflammatory factors such as interleukin-1 (IL-1), IL-6, IL-12, C-X-C motif chemokine ligand 10 (CXCL10), C-C motif ligand 3 (CCL3), CCL5, CCL2, TNF-alpha, CXCR6, XCR1, and CCR1, causing chronic inflammation and brain damage ( Bouças et al, 2020 ; Coperchini et al, 2020 ; Jakhmola et al, 2020 ; Wu et al, 2020b ; Khanmohammadi and Rezaei, 2021 ). Several of these chemokines and inflammatory factors are expressed in astrocytes, glia, neurons, neural stem cells, and oligodendrocytes ( Sowa and Tokarski, 2021 ). The cytokine storm, particularly the release of TNF-alpha, then leads to the suppression of B-cells and thus antibody production ( Kumar et al, 2021 ).…”