摘要：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
G93A
(
mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated
SOD1
G93A/
CCR2
Red fluorescence protein (RFP)/Wild type
(WT)
/
CX3CR1
Green fluorescence protein (GFP)/WT
-Tg mice, which heterozygously express
CCR2-RFP and
CX3CR1-GFP, and
SOD1
G93A/
CCR2
RFP/RFP-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
G93A/
CCR2
RFP/WT/
CX3CR1
GFP/WT 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.
