SIRT6 inhibition delays peripheral nerve recovery by suppressing migration, phagocytosis and M2-polarization of macrophages

Cell & Bioscience

Hui Zheng¹  Hao Sun¹  Zhenlin Li²  Jiawei Xu²  Ying Zou²  Jiaqi Zhang²  Lanya Fu²  Xianghai Wang³  Yizhou Xu⁴  Jiasong Guo⁵  Lixin Zhu⁶ 

[1] Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510700, Guangzhou, China;Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China;Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, 510515, Guangzhou, China;Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China;Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, 510515, Guangzhou, China;Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510700, Guangzhou, China;Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, 510515, Guangzhou, China;Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China;Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, 510515, Guangzhou, China;Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, China;Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China;Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, 510515, Guangzhou, China;Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, China;Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510700, Guangzhou, China;Key Laboratory of Mental Health of the Ministry of Education, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, 510515, Guangzhou, China;Department of Spine Orthopedics, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, China;

关键词: SIRT6;    Peripheral nerve injury;    Macrophages;    Migration;    Phagocytosis;    Polarization;   

DOI  :  10.1186/s13578-021-00725-y

来源: Springer

【 摘 要 】

BackgroundSilent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Prior evidences suggested that the anti-inflammatory function of SIRT6 after spinal cord and brain injury, and it plays a crucial role in macrophages polarization of adipose tissue and skin. However, the role of SIRT6 in macrophages involved peripheral nerve injury is still unknown. Given the prominent role of macrophages in peripheral nerve recovery, we aim to investigate the role of SIRT6 in the regulation of phenotypes shift and functions in macrophages after peripheral nerve injury.ResultsIn the present study, we first identified a significant increase of SIRT6 expression during nerve degeneration and macrophages phagocytosis. Next, we found nerve recovery was delayed after SIRT6 silencing by injected shRNA lentivirus into the crushed sciatic nerve, which exhibited a reduced expression of myelin-related proteins (e.g., MAG and MBP), severer myoatrophy of target muscles, and inferior nerve conduction compared to the shRNA control injected mice. In vitro, we found that SIRT6 inhibition by being treated with a selective inhibitor OSS_128167 or lentivirus transfection impairs migration and phagocytosis capacity of bone marrow-derived macrophages (BMDM). In addition, SIRT6 expression was discovered to be reduced after M1 polarization, but SIRT6 was enhanced after M2 polarization in the monocyte-macrophage cell line RAW264.7 and BMDM. Moreover, SIRT6 inhibition increased M1 macrophage polarization with a concomitant decrease in M2 polarization both in RAW264.7 and BMDM via activating NF-κB and TNF-α expression, and SIRT6 activation by UBCS039 treatment could shift the macrophages from M1 to M2 phenotype.ConclusionOur findings indicate that SIRT6 inhibition impairs peripheral nerve repair through suppressing the migration, phagocytosis, and M2 polarization of macrophages. Therefore, SIRT6 may become a favorable therapeutic target for peripheral nerve injury.

【 授权许可】

CC BY