期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-96064-6
关键词
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资金
- JSPS KAKENHI [JP16K09694, JP19K07963]
- Japan Society for the Promotion of Science
The study demonstrates that CCR2(+) and CX3CR1(+) macrophages play a neuroprotective role in ALS by clearing mSOD1 from peripheral nerves, which could be significant for the treatment of ALS.
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.
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