Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Charles L Howe; Reghann G. LaFrance-Corey; Emma N Goddery; Kanish Mirchia

The production of CCL2 by neurons during acute encephalitis may play a role in more than just leukocyte recruitment. For example, hippocampal neurons express CCR2 [21] and CCL2 directly enhances both NMDA receptor-and AMPA receptor-mediated excitatory postsynaptic potentials [30] . This suggests that the earliest stages of hippocampal circuit dysregulation associated with acute TMEV infection may be triggered locally by neuronal CCL2 acting in a autocrine fashion [31, 32] . In this context, it is notable that CCL2 immunoreactivity is strongly upregulated in CA1 neuron apical dendrite tufts located in the stratum lacunosum moleculare at 6 hr after infection (Figure 2 ). This layer is an important site of integration between the entorhinal cortex and CA1 pyramidal neurons (the perforant pathway) and is of fundamental importance to spatial and episodic memory formation [33] . It is also the site of GABAergic interneurons that are strongly activated by both entorhinal cortex and CA3-derived Schaffer collateral inputs [34] . These interneurons exhibit both AMPA receptor and NMDA receptor excitatory postsynaptic potentials [35] and are maximally activated at the theta oscillation peak and at the gamma oscillation trough [36] . These cells appear to mediate a robust feedforward inhibition that controls the size and timing of excitatory inputs onto CA1 neurons [37] and synchronizes network firing to theta frequency [34, 36] . Given the important role for hippocampal theta oscillations in learning and memory [38] , it is likely that acute production of CCL2 in the stratum lacunosum moleculare would disrupt cognitive performance. It is also notable that neuronal CCL2 production has been observed following kainic acid- [39] and pilocarpine-mediated seizure induction [40] in rodents and both CCL2 and CCR2 are increased in tissue resected from humans with intractable epilepsy [41, 42] . Inhibition of either CCL2 production or CCR2 signaling suppressed seizures in a mouse model of systemic inflammation and mesial temporal lobe epilepsy [43] . Indeed, Caleo and colleagues have recently suggested that CCL2 "may act as a master regulator of inflammatory processes in the epileptic brain by both directly promoting hyperexcitability and regulating the activity of downstream inflammatory effectors" [43]. Our findings echo this concept and add a third role in which hyperacute neuronal CCL2 production mediates CCR2-dependent inflammatory monocyte trafficking into the brain, resulting in the creation of an environment that further disrupts neural function and induces pyramidal neuron death [4, 7] .