Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression.

Macrophages expressing C-C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2 macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1 (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1/CCR2/CX3CR1-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1/CCR2-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1/CCR2/CX3CR1 mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2 macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2 and CX3CR1 macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.