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To identify the functional role of CCR2<jats:sup>+<\/jats:sup> macrophages in the pathomechanisms of ALS, we used an ALS animal model, <jats:italic>mutant Cu\/Zn superoxide dismutase 1<\/jats:italic><jats:sup><jats:italic>G93A<\/jats:italic><\/jats:sup> (<jats:italic>mSOD1<\/jats:italic>)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated <jats:italic>SOD1<\/jats:italic><jats:sup>G93A<\/jats:sup>\/<jats:italic>CCR2<\/jats:italic><jats:sup><jats:italic>Red fluorescence protein (<\/jats:italic>RFP)\/Wild type <jats:italic>(WT)<\/jats:italic><\/jats:sup>\/<jats:italic>CX3CR1<\/jats:italic><jats:sup><jats:italic>Green fluorescence protein (GFP)\/WT<\/jats:italic><\/jats:sup>-Tg mice, which heterozygously express <jats:italic>CCR2-RFP<\/jats:italic> and <jats:italic>CX3CR1-GFP<\/jats:italic>, and <jats:italic>SOD1<\/jats:italic><jats:sup>G93A<\/jats:sup>\/<jats:italic>CCR2<\/jats:italic><jats:sup>RFP\/RFP<\/jats:sup>-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In <jats:italic>mSOD1<\/jats:italic>-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of <jats:italic>SOD1<\/jats:italic><jats:sup>G93A<\/jats:sup>\/<jats:italic>CCR2<\/jats:italic><jats:sup>RFP\/WT<\/jats:sup>\/<jats:italic>CX3CR1<\/jats:italic><jats:sup>GFP\/WT<\/jats:sup> 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<jats:sup>+<\/jats:sup> macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient <jats:italic>mSOD1<\/jats:italic>-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive <jats:italic>mSOD1<\/jats:italic>-Tg mice. CCR2-deficient <jats:italic>mSOD1<\/jats:italic>-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2<jats:sup>+<\/jats:sup> and CX3CR1<jats:sup>+<\/jats:sup> macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.<\/jats:p>","DOI":"10.1038\/s41598-021-96064-6","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:03:40Z","timestamp":1628762620000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Clearance of peripheral nerve misfolded mutant protein by infiltrated macrophages correlates with motor neuron disease progression"],"prefix":"10.1038","volume":"11","author":[{"given":"Wataru","family":"Shiraishi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senri","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Kobayakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Isobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Matsushita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-ichi","family":"Kira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"96064_CR1","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/S1474-4422(13)70036-X","volume":"12","author":"MR Turner","year":"2013","unstructured":"Turner, M. 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