CCL21-CCR7 blockade prevents neuroinflammation and degeneration in Parkinson’s disease models

Parkinson's disease (PD) is a progressive degenerative disease of the central nervous system associated with neuroinflammation and microglial cell activation. Chemokine signaling regulates neuron-glia communication and triggers a microglial inflammatory profile. Herein, we identified the neuronal chemokine CCL21 as a major cause of microglial cell imbalance through the CCR7 receptor pathway with therapeutic implications for PD. In humans, we found that CCL21 transcript expression was increased in dopaminergic neurons (DANs) of the substantia nigra in PD patients. CCL21 and CCR7 expressions were spatially associated with brain regional vulnerability to synucleinopathies, as well as with the expression of microglial activation, neuroinflammation, and degeneration-related genes. Also, in mouse models of PD, we showed that CCL21 was overexpressed in DANs in vivo and in vitro. Mechanistically, neuronal CCL21 was shown to regulate microglial cell migration, proliferation, and activation in a CCR7-dependent manner through both canonical (PI3K/AKT) and non-canonical (ERK1/2/JNK) signaling pathways. Finally, we demonstrated that navarixin, a clinically relevant chemokine inhibitor with high affinity for the CCR7 receptor, could block CCL21 effects on microglia and prevent neurodegeneration and behavioral deficits in two mouse models of PD induced with either α-synuclein oligomers (αSynO) or 3,4-dihydroxyphenylacetaldehyde (DOPAL). Altogether, our data indicate that navarixin blocks CCL21/CCR7-mediated neuron-microglia communication and could be used as a therapeutic strategy against PD.