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Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice

The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Macrophages and microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 p...

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Autores principales: Yao, Anhui, Liu, Fangfang, Chen, Kun, Tang, Liang, Liu, Ling, Zhang, Kun, Yu, Caiyong, Bian, Ganlan, Guo, Hongmin, Zheng, Jingjing, Cheng, Peng, Ju, Gong, Wang, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121443/
https://www.ncbi.nlm.nih.gov/pubmed/24853068
http://dx.doi.org/10.1007/s13311-013-0254-x
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author Yao, Anhui
Liu, Fangfang
Chen, Kun
Tang, Liang
Liu, Ling
Zhang, Kun
Yu, Caiyong
Bian, Ganlan
Guo, Hongmin
Zheng, Jingjing
Cheng, Peng
Ju, Gong
Wang, Jian
author_facet Yao, Anhui
Liu, Fangfang
Chen, Kun
Tang, Liang
Liu, Ling
Zhang, Kun
Yu, Caiyong
Bian, Ganlan
Guo, Hongmin
Zheng, Jingjing
Cheng, Peng
Ju, Gong
Wang, Jian
author_sort Yao, Anhui
collection PubMed
description The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Macrophages and microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Programmed cell death 1 (PD-1) is a critical immune inhibitory receptor involved in innate and adaptive immune responses. However, whether PD-1 is involved in the modulation of macrophage/microglial polarization is unknown. In this study, the mRNA levels of pd1 gradually increased after SCI, and PD-1 protein was found in macrophages/microglia in injured spinal cord sections. PD-1 knockout (KO) mice showed poor locomotor recovery after spinal cord crushing compared with wild-type mice. M1-type macrophages/microglia accumulated in greater numbers in the injured spinal cord of PD-1-KO mice. Under polarized stimulation, induced expression of PD-1 occurred in cultured macrophages and microglia. PD-1 suppressed M1 polarization by reducing the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and promoted M2 polarization by increasing STAT6 phosphorylation. In PD-1-KO mice, the M1 response was enhanced via the activation of STAT1 and nuclear factor-kappa B. Furthermore, PD-1 played various roles in phagocytosis in macrophages and microglia. Therefore, our results suggest that PD-1 signaling plays an important role in the regulation of macrophage/microglial polarization. Thus, deregulated PD-1 signaling may induce the polarization of macrophages/microglia toward the M1 phenotype. Overall, our results provide new insights into the modulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapies for SCI via the regulation of macrophage/microglial polarization through PD-1 signaling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13311-013-0254-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-41214432014-08-18 Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice Yao, Anhui Liu, Fangfang Chen, Kun Tang, Liang Liu, Ling Zhang, Kun Yu, Caiyong Bian, Ganlan Guo, Hongmin Zheng, Jingjing Cheng, Peng Ju, Gong Wang, Jian Neurotherapeutics Original Article The inflammatory response following spinal cord injury (SCI) involves the activation of resident microglia and the infiltration of macrophages. Macrophages and microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Programmed cell death 1 (PD-1) is a critical immune inhibitory receptor involved in innate and adaptive immune responses. However, whether PD-1 is involved in the modulation of macrophage/microglial polarization is unknown. In this study, the mRNA levels of pd1 gradually increased after SCI, and PD-1 protein was found in macrophages/microglia in injured spinal cord sections. PD-1 knockout (KO) mice showed poor locomotor recovery after spinal cord crushing compared with wild-type mice. M1-type macrophages/microglia accumulated in greater numbers in the injured spinal cord of PD-1-KO mice. Under polarized stimulation, induced expression of PD-1 occurred in cultured macrophages and microglia. PD-1 suppressed M1 polarization by reducing the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and promoted M2 polarization by increasing STAT6 phosphorylation. In PD-1-KO mice, the M1 response was enhanced via the activation of STAT1 and nuclear factor-kappa B. Furthermore, PD-1 played various roles in phagocytosis in macrophages and microglia. Therefore, our results suggest that PD-1 signaling plays an important role in the regulation of macrophage/microglial polarization. Thus, deregulated PD-1 signaling may induce the polarization of macrophages/microglia toward the M1 phenotype. Overall, our results provide new insights into the modulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapies for SCI via the regulation of macrophage/microglial polarization through PD-1 signaling. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13311-013-0254-x) contains supplementary material, which is available to authorized users. Springer US 2014-05-23 2014-07 /pmc/articles/PMC4121443/ /pubmed/24853068 http://dx.doi.org/10.1007/s13311-013-0254-x Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Article
Yao, Anhui
Liu, Fangfang
Chen, Kun
Tang, Liang
Liu, Ling
Zhang, Kun
Yu, Caiyong
Bian, Ganlan
Guo, Hongmin
Zheng, Jingjing
Cheng, Peng
Ju, Gong
Wang, Jian
Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title_full Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title_fullStr Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title_full_unstemmed Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title_short Programmed Death 1 Deficiency Induces the Polarization of Macrophages/Microglia to the M1 Phenotype After Spinal Cord Injury in Mice
title_sort programmed death 1 deficiency induces the polarization of macrophages/microglia to the m1 phenotype after spinal cord injury in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121443/
https://www.ncbi.nlm.nih.gov/pubmed/24853068
http://dx.doi.org/10.1007/s13311-013-0254-x
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