Microglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination

R Ronzano,L Richard,C Lubetzki,T Roux,M S Aigrot,F X Lejeune,A Desmazières,M Thetiot,J M Vallat,E Mazuir

doi:10.1038/s41467-021-25486-7

Abstract

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct site of interaction between microglia and axons, in both mouse and human tissues. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglia-node interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury.

Highlights

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity
By performing immunostainings and 3D reconstruction on adult mouse fixed tissue, we first observed that microglia (Iba1+ cells) contact nodes of Ranvier (AnkyrinG+ structures surrounded by paranodal Caspr+ staining) in central nervous system (CNS) gray as well as white matter, confirming and extending a previous observation in rat corpus callosum[33]
Longitudinal views of nodes delineated by the paranodal loops on both sides and contacted by microglial processes show that these processes directly contact the nodal axolemma (Fig. 1B) and that the microglial process sometimes extends towards the first paranodal loops (Fig. 1Bii–ii′)

Summary

Introduction

The resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury. Cells with a pro-inflammatory signature stimulate proliferation and recruitment of oligodendrocyte precursors cells (OPCs) towards the lesion, whereas pro-regenerative microglial cells promote OPCs differentiation into myelinating oligodendrocytes[14,15,16,22] These experimental data are consistent with results showing an enrichment in proregenerative microglia in remyelinating lesions[14,15,16]. The axon initial segment (AIS) has been identified as a site of microglia-neuron contact, with description of microglial processes overlapping AIS in healthy brain, which vary following brain injury and inflammation[30,31]

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Results

Conclusion