Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.

<h4>Background</h4>Although macrophages (MPhi) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MPhi subpopulations at the lesion site have further co...

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Autores principales:	Ravid Shechter, Anat London, Chen Varol, Catarina Raposo, Melania Cusimano, Gili Yovel, Asya Rolls, Matthias Mack, Stefano Pluchino, Gianvito Martino, Steffen Jung, Michal Schwartz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/984621802b204291b59412b4a6853944
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spelling	oai:doaj.org-article:984621802b204291b59412b4a68539442021-11-25T05:37:34ZInfiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.1549-12771549-167610.1371/journal.pmed.1000113https://doaj.org/article/984621802b204291b59412b4a68539442009-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19636355/?tool=EBIhttps://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>Although macrophages (MPhi) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MPhi subpopulations at the lesion site have further contributed to the controversy and led to the common view of MPhi as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MPhi contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MPhi is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI.<h4>Methods and findings</h4>We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MPhi on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MPhi. We followed the infiltration of the monocyte-derived MPhi to the injured site and characterized their spatial distribution and phenotype. Increasing the naïve monocyte pool by either adoptive transfer or CNS-specific vaccination resulted in a higher number of spontaneously recruited cells and improved recovery. Selective ablation of infiltrating monocyte-derived MPhi following SCI while sparing the resident microglia, using either antibody-mediated depletion or conditional ablation by diphtheria toxin, impaired recovery. Reconstitution of the peripheral blood with monocytes resistant to ablation restored the lost motor functions. Importantly, the infiltrating monocyte-derived MPhi displayed a local anti-inflammatory beneficial role, which was critically dependent upon their expression of interleukin 10.<h4>Conclusions</h4>The results of this study attribute a novel anti-inflammatory role to a unique subset of infiltrating monocyte-derived MPhi in SCI recovery, which cannot be provided by the activated resident microglia. According to our results, limited recovery following SCI can be attributed in part to the inadequate, untimely, spontaneous recruitment of monocytes. This process is amenable to boosting either by active vaccination with a myelin-derived altered peptide ligand, which indicates involvement of adaptive immunity in monocyte recruitment, or by augmenting the naïve monocyte pool in the peripheral blood. Thus, our study sheds new light on the long-held debate regarding the contribution of MPhi to recovery from CNS injuries, and has potentially far-reaching therapeutic implications.Ravid ShechterAnat LondonChen VarolCatarina RaposoMelania CusimanoGili YovelAsya RollsMatthias MackStefano PluchinoGianvito MartinoSteffen JungMichal SchwartzPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 6, Iss 7, p e1000113 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Ravid Shechter Anat London Chen Varol Catarina Raposo Melania Cusimano Gili Yovel Asya Rolls Matthias Mack Stefano Pluchino Gianvito Martino Steffen Jung Michal Schwartz Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
description	<h4>Background</h4>Although macrophages (MPhi) are known as essential players in wound healing, their contribution to recovery from spinal cord injury (SCI) is a subject of debate. The difficulties in distinguishing between different MPhi subpopulations at the lesion site have further contributed to the controversy and led to the common view of MPhi as functionally homogenous. Given the massive accumulation in the injured spinal cord of activated resident microglia, which are the native immune occupants of the central nervous system (CNS), the recruitment of additional infiltrating monocytes from the peripheral blood seems puzzling. A key question that remains is whether the infiltrating monocyte-derived MPhi contribute to repair, or represent an unavoidable detrimental response. The hypothesis of the current study is that a specific population of infiltrating monocyte-derived MPhi is functionally distinct from the inflammatory resident microglia and is essential for recovery from SCI.<h4>Methods and findings</h4>We inflicted SCI in adult mice, and tested the effect of infiltrating monocyte-derived MPhi on the recovery process. Adoptive transfer experiments and bone marrow chimeras were used to functionally distinguish between the resident microglia and the infiltrating monocyte-derived MPhi. We followed the infiltration of the monocyte-derived MPhi to the injured site and characterized their spatial distribution and phenotype. Increasing the naïve monocyte pool by either adoptive transfer or CNS-specific vaccination resulted in a higher number of spontaneously recruited cells and improved recovery. Selective ablation of infiltrating monocyte-derived MPhi following SCI while sparing the resident microglia, using either antibody-mediated depletion or conditional ablation by diphtheria toxin, impaired recovery. Reconstitution of the peripheral blood with monocytes resistant to ablation restored the lost motor functions. Importantly, the infiltrating monocyte-derived MPhi displayed a local anti-inflammatory beneficial role, which was critically dependent upon their expression of interleukin 10.<h4>Conclusions</h4>The results of this study attribute a novel anti-inflammatory role to a unique subset of infiltrating monocyte-derived MPhi in SCI recovery, which cannot be provided by the activated resident microglia. According to our results, limited recovery following SCI can be attributed in part to the inadequate, untimely, spontaneous recruitment of monocytes. This process is amenable to boosting either by active vaccination with a myelin-derived altered peptide ligand, which indicates involvement of adaptive immunity in monocyte recruitment, or by augmenting the naïve monocyte pool in the peripheral blood. Thus, our study sheds new light on the long-held debate regarding the contribution of MPhi to recovery from CNS injuries, and has potentially far-reaching therapeutic implications.
format	article
author	Ravid Shechter Anat London Chen Varol Catarina Raposo Melania Cusimano Gili Yovel Asya Rolls Matthias Mack Stefano Pluchino Gianvito Martino Steffen Jung Michal Schwartz
author_facet	Ravid Shechter Anat London Chen Varol Catarina Raposo Melania Cusimano Gili Yovel Asya Rolls Matthias Mack Stefano Pluchino Gianvito Martino Steffen Jung Michal Schwartz
author_sort	Ravid Shechter
title	Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
title_short	Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
title_full	Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
title_fullStr	Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
title_full_unstemmed	Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
title_sort	infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/984621802b204291b59412b4a6853944
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Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice.

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