TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells

Wei, Can; Cai, Shiyi; Fang, Ling

doi:10.1016/j.bbrc.2020.10.062

“…M1-type macrophages were induced by treatment with LPS (100 ng/ml) and IFN-γ (20 ng/ml) in the cell medium of DMEMF/12 containing 10% FBS for 24 h. M2-type macrophages were induced by treatment with IL-4 (20 ng/ml) and IL-13 (20 ng/ml) in the cell medium of DMEMF/12 containing 10% FBS for 24 h, as previously reported [ 45 ]. To study the effect of SIRT6 inhibition in macrophages polarization, 200 μM OSS_128167 was added into M1-stimulated medium or M2-stimulated medium.…”

Section: Methodssupporting

confidence: 62%

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

Zou,

Zhang,

Xu

et al. 2021

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Background Silent 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. Results In 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. Conclusion Our 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.

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“…The transfection process was carried out as described previously. 26 Then, qRT‐PCR was used to determine the efficiency of gene knockout and overexpression.…”

Section: Methodsmentioning

confidence: 99%

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

Yuan

¹

,

Wei

²

,

Liu

³

et al. 2021

Self Cite

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Objectives Evidences demonstrate that sorafenib alleviates liver fibrosis via inhibiting HSC activation and ECM accumulation. The underlying mechanism remains unclear. Ferroptosis, a novel programmed cell death, regulates diverse physiological/pathological processes. In this study, we aim to investigate the functional role of HSC ferroptosis in the anti‐fibrotic effect of sorafenib. Materials and Methods The effects of sorafenib on HSC ferroptosis and ECM expression were assessed in mouse model of liver fibrosis induced by CCl 4 . In vitro, Fer‐1 and DFO were used to block ferroptosis and then explored the anti‐fibrotic effect of sorafenib by detecting α‐SMA, COL1α1 and fibronectin proteins. Finally, HIF‐1α siRNA, plasmid and stabilizers were applied to assess related signalling pathway. Results Sorafenib attenuated liver injury and ECM accumulation in CCl 4 ‐induced fibrotic livers, accompanied by reduction of SLC7A11 and GPX4 proteins. In sorafenib‐treated HSC‐T6 cells, ferroptotic events (depletion of SLC7A11, GPX4 and GSH; accumulation iron, ROS and MDA) were discovered. Intriguingly, these ferroptotic events were not appeared in hepatocytes or macrophages. Sorafenib‐elicited HSC ferroptosis and ECM reduction were abrogated by Fer‐1 and DFO. Additionally, both HIF‐1α and SLC7A11 proteins were reduced in sorafenib‐treated HSC‐T6 cells. SLC7A11 was positively regulated by HIF‐1α, inactivation of HIF‐1α/SLC7A11 pathway was required for sorafenib‐induced HSC ferroptosis, and elevation of HIF‐1α could inhibit ferroptosis, ultimately limited the anti‐fibrotic effect. Conclusions Sorafenib triggers HSC ferroptosis via HIF‐1α/SLC7A11 signalling, which in turn attenuates liver injury and fibrosis.

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“…Recent studies have revealed that TRPM7 also has effects on the functions of macrophages and plays a regulatory role for the homeostasis of the immune system [40][41][42]. Li et al stated that TRPM7 blockade is an essential factor in the transformation of macrophages into M2 phenotype [40].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have revealed that TRPM7 also has effects on the functions of macrophages and plays a regulatory role for the homeostasis of the immune system [40][41][42]. Li et al stated that TRPM7 blockade is an essential factor in the transformation of macrophages into M2 phenotype [40]. On the contrary, Schilling et al suggested that TRPM7 channel activity is required for the macrophage polarization event where bone marrow-derived macrophages transform into the M2-type macrophage phenotype [42].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of TRPM7 Expression and Factor XIIIa-Expressing Tumor-Associated Macrophages in Gastric Cancer

Çalık

¹

,

Çalık

²

,

Artaş

³

et al. 2021

Gastroenterology Research and Practice

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Purpose. TRPM7 is known to play a key role in tumor progression by regulating cellular proliferation, migration, and invasion in various cancer cell lines. However, there are no comprehensive clinical studies about the effect of TRPM7 expression on gastric cancer (GC) prognosis. In this study, it was aimed at investigating the effect of TRPM7 expression on prognosis in GC patients. Additionally, for the first time, it was investigated whether the density of Factor XIIIa-expressing tumor-associated macrophages (TAMs) in GC has an effect on the biological behaviour of the tumor. Methods. TRPM7 expression and Factor XIIIa-expressing TAM density were immunohistochemically evaluated in paraffin-embedded tumor tissues of 204 GC patients undergoing surgery at a single institution. Results. Tumor size was clearly higher in cases with high TRPM7 expression than those with low expression ( p < 0.001 , Mann-Whitney U ). TRPM7 overexpression was closely related to high depth of tumor invasion ( p < 0.001 , ANOVA), increased lymph node metastasis ( p < 0.001 , ANOVA), and high distant metastasis rate ( p < 0.001 , Mann-Whitney U ). These findings exposed that high TRPM7 expression is effective in the progression and aggressiveness of GC. In addition, while high CD8+ TIL density affects the prognosis positively, it was determined that high Factor XIIIa+ TAM density negatively affects the prognosis of patients with GC. Furthermore, multivariate analyses revealed TRPM7 overexpression was independently related with short overall (HR 9.64, 95% CI 5.74–16.19, p < 0.001 ) and disease-free survival (HR 5.67, 95% CI 3.61-8.92, p < 0.001 ) in GC patients. Conclusions. Our data suggest that high TRPM7 expression is closely related to progressive tumor behaviour in GC and independently negatively affects survival in patients. In addition, it was determined that a high density of Factor XIIIa+ TAMs negatively affects the prognosis of patients with GC.

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TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells

Cited by 21 publications

References 29 publications

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

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

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

Prognostic Value of TRPM7 Expression and Factor XIIIa-Expressing Tumor-Associated Macrophages in Gastric Cancer

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