Vesicle-Mediated Transport and Release of CCL21 in Endangered Neurons: A Possible Explanation for Microglia Activation Remote from a Primary Lesion

Abstract

Whenever neurons in the CNS are injured, microglia become activated. In addition to local activation, microglia remote from the primary lesion site are stimulated. Because this so-called secondary activation of microglia is instrumental for long-term changes after neuronal injury, it is important to understand how microglia activity is controlled. The remote activation of microglia implies that the activating signals are transported along neuronal projections. However, the identity of these signals has not yet been identified. It is shown here that glutamate-treated neurons rapidly express and release the chemokine CCL21. We also provide evidence that neuronal CCL21 is packed in vesicles and transported throughout neuronal processes to reach presynaptic structures. Chemotaxis assays show that functional CCL21 is released from endangered neurons and activate microglia via the chemokine receptor CXCR3. Based on these findings, we suggest that neuronal CCL21 is important in directed neuron-microglia signaling and that this communication could account for the remote activation of microglia, far distant from a primary lesion.

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

“…Cortical neurons were prepared from embryonic mouse brains (E15-16) as described before (de Jong et al, 2005). Neurons were used after 6 days in culture.…”

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

“…Neuronal cysteine-cysteine chemokine ligand 21 (CCL21) is synthesized by damaged neurons; following packaging in vesicles and transport, it reaches presynaptic sites, where it is released to activate microglia at sites distant from the primary lesion. [72][73][74][75] Spinal cord contusion injury at T9 increases CCL21 signal in excitatory neurons of the dorsal horn and in spinal parenchyma at both the T9 and L4 spinal segments. 54 Distal release of CCL21 produced following SCI by injured neurons at the trauma site has been proposed as a molecular mechanism that triggers microglial activation at spinal segments far from the site of injury, and in the thalamus in association with pain phenomena.…”

P2X4 purinoceptor signaling in chronic pain

“…Significant advances have been made towards understanding how injury to a nerve signals to the dorsal horn causing increased P2X4R expression in microglia. One such neuronmicroglia signaling molecule is CCL21, a microglia-activating chemokine released from injured neurons [5,20]. A recent study by Biber et al [5] reported that following injury to a peripheral nerve, CCL21 expression was significantly increased in small diameter neurons in the dorsal root ganglia and in primary afferent nerve terminals in the spinal dorsal horn, but not in microglia or in astrocytes.…”