Abstract
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.
Highlights
In the injured peripheral nerve, the axons and myelin will undergo fragmentation and degeneration and the debris have to be cleared by phagocytosis of macrophages and Schwann cells [1, 2]
Silent information regulator 6 (SIRT6) expression is up‐regulated and accompanied with macrophages infiltration in the transected sciatic nerve As well known, when axons are injured by nerve transection or nerve crush, the distal nerve segment fragments and degenerates, eventually myelin and axonal debris are predominantly cleared by macrophages (Fig. 1A) [1]
To determine whether SIRT6 is related to macrophages infiltration, we examined the SIRT6 and F4/80 expression as well as expression of myelin-related proteins (e.g., MAG, MBP, and c-Jun) by Western blotting
Summary
In the injured peripheral nerve, the axons and myelin will undergo fragmentation and degeneration and the debris have to be cleared by phagocytosis of macrophages and Schwann cells [1, 2]. M1 macrophages are associated with pro-inflammatory function and neurodegenerative outcome, whereas M2 macrophages are broadly known as anti-inflammatory cells for promoting nerve repair [7]. The migration, phagocytosis and polarization of macrophages play important roles in nerve regeneration. The outcome of SIRT6 inhibition in macrophages as well as its roles in peripheral nerve injury are still unclear. 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. 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
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