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

Abstract 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 sup...

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Autores principales:	Wataru Shiraishi, Ryo Yamasaki, Yu Hashimoto, Senri Ko, Yuko Kobayakawa, Noriko Isobe, Takuya Matsushita, Jun-ichi Kira
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/38e6c8f790e142f19d800032a48c1af0
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spelling	oai:doaj.org-article:38e6c8f790e142f19d800032a48c1af02021-12-02T16:28:50ZClearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression10.1038/s41598-021-96064-62045-2322https://doaj.org/article/38e6c8f790e142f19d800032a48c1af02021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96064-6https://doaj.org/toc/2045-2322Abstract 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.Wataru ShiraishiRyo YamasakiYu HashimotoSenri KoYuko KobayakawaNoriko IsobeTakuya MatsushitaJun-ichi KiraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wataru Shiraishi Ryo Yamasaki Yu Hashimoto Senri Ko Yuko Kobayakawa Noriko Isobe Takuya Matsushita Jun-ichi Kira Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
description	Abstract 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.
format	article
author	Wataru Shiraishi Ryo Yamasaki Yu Hashimoto Senri Ko Yuko Kobayakawa Noriko Isobe Takuya Matsushita Jun-ichi Kira
author_facet	Wataru Shiraishi Ryo Yamasaki Yu Hashimoto Senri Ko Yuko Kobayakawa Noriko Isobe Takuya Matsushita Jun-ichi Kira
author_sort	Wataru Shiraishi
title	Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
title_short	Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
title_full	Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
title_fullStr	Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
title_full_unstemmed	Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
title_sort	clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/38e6c8f790e142f19d800032a48c1af0
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_version_	1718383922981634048

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

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