Current perspectives on microglia-neuron communication in the central nervous system: Direct and indirect modes of interaction

Abstract

Background: The incessant communication that takes place between microglia and neurons is essential the development, maintenance, and pathogenesis of the central nervous system (CNS). As mobile phagocytic cells, microglia serve a critical role in surveilling and scavenging the neuronal milieu to uphold homeostasis.

Aim of review: This review aims to discuss the various mechanisms that govern the interaction between microglia and neurons, from the molecular to the organ system level, and to highlight the importance of these interactions in the development, maintenance, and pathogenesis of the CNS.

Key scientific concepts of review: Recent research has revealed that microglia-neuron interaction is vital for regulating fundamental neuronal functions, such as synaptic pruning, axonal remodeling, and neurogenesis. The review will elucidate the intricate signaling pathways involved in these interactions, both direct and indirect, to provide a better understanding of the fundamental mechanisms of brain function. Furthermore, gaining insights into these signals could lead to the development of innovative therapies for neural disorders.

Keywords: CNS; Interaction; Microglia; Molecular mechanisms; Neuroinflammation; Neuron.

Graphical abstract

Fig. 1

Basic functions of microglia in microglia-neuron interaction. (A) Synaptic pruning. Highly ramified microglial processes transiently and repetitively contact with synapses, enwrap above them, and then exert phagocytosis. (B) Axonal remodeling. Microglial processes are directly connected to the axons and participant in axonal guidance and remodeling. (C) Neurogenesis. Microglia participate in prompting neurogenesis by phagocytosing apoptotic SGZ newborn cells, as well as releasing important trophic factors. AIS, axon initial segment.

Fig. 2

Overview of indirect and direct microglia-neuron interaction. (A) Long-distance indirect communications between microglia and neurons through other organs, mainly the gut. Within the CNS, indirect microglia-neuron interactions include (B) Communication through intermediate cells (e.g., astrocytes, oligodendrocytes, T cells) (C) Interaction via soluble factors (e.g., peptides, trophic factors, neurotransmitters, extracellular vehicles, cytokines). (D) Direct membrane-membrane contacts between microglia and neurons in a compartment-dependent manner. AIS, axon initial segment.

Fig. 3

Remote microglia-neuron interaction through microbiota-gut-brain axis and involved signaling pathways. The colonized microbes in the gut communicate with the brain via the vagus nerve system and immune system, involving microbial metabolites such as short-chain fatty acids (SCFAs), and various transmitters (e.g., polyamines, and amino acids). After crossing the BBB, the LPS and SCFAs may activate microglia to either release the cytokines to affect the state of neurons via TLR4 signaling or change the morphology of the microglia to engulf the neuronal synapse via SCFAs-mediated signaling. In addition, GLP-1, regulated by gut microbiota, also contributes to remote microglia-neuron interaction. “P” labeling is attached to the molecules that are phosphorylated due to signaling transduction. BBB, blood–brain barrier; GLP-1, Glucagon-like peptide-1; GPR41, G protein-coupled receptor 41; GPR43, G protein-coupled receptor 43; IL-1β, interleukin 1 beta; LPS, Lipopolysaccharide; SCFAs: short-chain fatty acids; TLR4, Toll-like receptor4; TNF-α, tumor necrosis factor alpha.

Fig. 4

Local microglia-neuron interaction through intermediate cells and involved signaling pathways. (A) Astrocyte-mediated microglia-neuron interaction. Astrocytes participate in microglia-neuron interaction through MEGF10/MERTK pathway, IL-33/ST2 pathway, and Wnt/β-catenin signaling pathway. (B) T cell-medicated microglia-neuron interaction may be though JAK/STAT signaling. ABCA1, ATP binding cassette subfamily A member 1; AKT, protein kinase B; APC, adenomatous polyposis coli; CCL2, monocyte chemoattractant protein-1; IFNγ, interferon-gamma; IL-33, interleukin 33; JAK, Janus kinase; LRP5/6, lipoprotein receptor-related protein; MEGF10, Multiple EGF-like domains 10; MERTK, MER Proto-Oncogene tyrosine kinase; ST2, suppression of tumorigenicity 2; STAT, signal transducer and activator of transcription; TCL/LEF, β-catenin-T-cell factor/lymphoid enhancer-binding factor.

Fig. 5

Local microglia-neuron interaction through intermediate soluble factors and involved signaling pathways. Most intermediate soluble factors that contribute to microglia-neuron interaction come from microglia. The involved signaling includes BDNF/TrkB signaling, IL-6 trans-signaling, and EVs. “P” labeling is attached to the molecules that are phosphorylated due to signaling transduction. Akt, protein kinase B; BDNF, brain-derived neurotrophic factor; CaMKII, Calcium-calmodulin-dependent protein kinase II; CREB, cAMP response element binding protein; ERK, extracellular-signal-regulated kinase; EVs, Extracellular-vehicles; Gab1, Grb2 associated binder-1; Grb2, growth factor receptor bound protein 2; IL-6, interleukin 6; MEK, MAP kinase-ERK kinase; PI3K, Phosphoinositide 3-kinase; PLCγ, phospholipase C-γ; TrkB, tropomyosin receptor kinase B.

Fig. 6

Compartment-dependent direct microglia-neuron interaction. (A) complement system C3, C1q; CD47/SIRPα, CX3CL1/CX3CR1, and CD200/CD200R signaling have been confirmed play essential roles in microglia-synapse/dendrite interactions. (B) Microglia-soma interactions have complicated structures involving microglial P2Y12Rs, neuronal anchored mitochondria, endoplasmic reticulum plasma membrane, mitochondrion-derived vesicles, as well as Kv2.1 and Kv2.2 proteins. The specialized structure has been confirmed in a study (Csaba Cserép et al, 2020). (C) Microglial TREM2 senses anionic lipids and Aβ in AD pathology. TREM2/DAP12 contributes to protecting against damage-associated demyelination. However, the localization of involved molecular elements has not yet been confirmed. AIS, axon initial segment; DAP12, DNAX-binding protein of 12 kDa; SIRPα, signal-regulatory protein-α; TOM20, translocase Of Outer Mitochondrial Membrane 20; TREM2, triggering receptor expressed on myeloid cells 2.