Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis

Torres‐Hernandez, Alejandro; Wang, Wei; Nikiforov, Yuri E.; Tejada, Karla; Torres, Luisana E.; Kalabin, Aleksandr; Wu, Yue; Haq, Muhammad Israr Ul; Khan, Mohammed Yunus; Zhao, Zhen; Su, Wenyu; Camargo, Jimmy; Hundeyin, Mautin; Diskin, Brian; Adam, Salma; Rossi, Juan Andres Kochen; Kurz, Emma; Aykut, Berk; Shadaloey, Sorin A. A.; Leinwand, Joshua; Miller, George

doi:10.1038/s41388-019-0734-5

Cited by 33 publications

(32 citation statements)

References 40 publications

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“…Moreover, these were associated with reduced hepatic expression of inflammatory markers such as Cd44 (Figure 5G and H at the gene and protein levels, respectively) and Sele (E-Selectin) (Figure 5G). In line with the potential role of SYK in the regulation of macrophage activation/polarization, 18,41 the hepatic expression of M1 markers Itgax (CD11C) and Tnf decreased, whereas the expression of the M2 marker Clec10a (CD301) did not change in MCDD-fed mSyk KO mice compared with MCDD-fed Wt mice (Figure 5G). As reported for 3BP2 deficiency (Figure 3G), the knockdown of SYK in myeloid cells strongly decreased the hepatic expression of Trem1 and Dap12, the priming of the fibrosis (Tgfb1 and Timp1), and oxidative stress (Cyba and Hmox1) (Figure 5G).…”

Section: The Knockdown Of Syk In Myeloid Cells Partially Prevented Liver Injury and Inflammation Induced By Mcdd Challengesupporting

confidence: 61%

“…Indeed, it has been shown that SYK inhibitors prevented HSC activation in vitro and in animal models of hepatic fibrosis. 17,18 However, the protective effects of SYK targeting seem to be more related to an effect on myeloid cells than on HSC because its deficiency in HSC (Lrat Cre Syk flox/flox ) did not mitigate the severity of fibrosis mediated by TAA treatment. 18 Interestingly, we also show that SYK deletion in myeloid cells prevents hepatic inflammation in cherubic mice expressing the 3BP2 G418R mutant (Sh3bp2 G418R knockin mice, equivalent to the G420R mutation in cherubism patients).…”

Section: Discussionmentioning

confidence: 99%

“…17,18 However, the protective effects of SYK targeting seem to be more related to an effect on myeloid cells than on HSC because its deficiency in HSC (Lrat Cre Syk flox/flox ) did not mitigate the severity of fibrosis mediated by TAA treatment. 18 Interestingly, we also show that SYK deletion in myeloid cells prevents hepatic inflammation in cherubic mice expressing the 3BP2 G418R mutant (Sh3bp2 G418R knockin mice, equivalent to the G420R mutation in cherubism patients). Indeed, SYK deletion in these mice mediates a drastic reduction in inflammatory foci number, macrophage recruitment, and hepatic expression of TNF-a, CCL2, and CD44.…”

Section: Discussionmentioning

confidence: 99%

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SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis

Luci

Vieira

Bourinet

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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This work reports that SYK-3BP2 pathway activity enhances the LPS-TLR4 responses in both hepatocytes and resident liver macrophages. This initiates the onset of local inflammation and contributes to liver accumulation of leukocytes. Targeting of 3BP2 or SYK prevents metabolic steatohepatitis features.BACKGROUND & AIMS: Spleen tyrosine kinase (SYK) signaling pathway regulates critical processes in innate immunity, but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate c-Abl Src homology 3 domain-binding protein-2 (3BP2) in both myeloid cells and hepatocytes in the onset of metabolic steatohepatitis.METHODS: Hepatic SYK-3BP2 pathway was evaluated in mouse models of metabolic-associated fatty liver diseases (MAFLD) and in obese patients with biopsy-proven MAFLD (n ¼ 33). Its role in liver complications was evaluated in Sh3bp2 KO and myeloid-specific Syk KO mice challenged with methionine and choline deficient diet and in homozygous Sh3bp2 KI/KI mice with and without SYK expression in myeloid cells.RESULTS: Here we report that hepatic expression of 3BP2 and SYK correlated with metabolic steatohepatitis severity in mice. 3BP2 deficiency and SYK deletion in myeloid cells mediated the same protective effects on liver inflammation, injury, and fibrosis priming upon diet-induced steatohepatitis. In primary hepatocytes, the targeting of 3BP2 or SYK strongly decreased the lipopolysaccharide-mediated inflammatory mediator expression and 3BP2-regulated SYK expression. In homozygous Sh3bp2 KI/KI mice, the chronic inflammation mediated by the proteasome-resistant 3BP2 mutant promoted severe hepatitis and liver fibrosis with augmented liver SYK expression. In these mice, the deletion of SYK in myeloid cells was sufficient to prevent these liver lesions. The hepatic expression of SYK is also up-regulated with metabolic steatohepatitis and correlates with liver macrophages in biopsy-proven MAFLD patients. CONCLUSIONS:Collectively, these data suggest an important role for the SYK-3BP2 pathway in the pathogenesis of chronic liver inflammatory diseases and highlight its targeting in hepatocytes and myeloid cells as a potential strategy to treat

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Section: The Knockdown Of Syk In Myeloid Cells Partially Prevented Liver Injury and Inflammation Induced By Mcdd Challengesupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis

Luci

Vieira

Bourinet

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…19,20 Besides, expression of genes that promote metastasis and vascular formation, such as GJA1 and SYK, was repressed ( Figure 7A and B). [21][22][23] In particular, expression of VEGFC, a positive regulator of lymph-node metastasis and lymphangiogenesis, 24,25 was downregulated in response to SLC39A4 absence ( Figure 7B). Inflammation and modulation of the immune microenvironment have key roles in influencing tumor progression.…”

Section: Downregulation Of Slc39a4 Expression Influenced the Signalinmentioning

confidence: 99%

Knockdown of SLC39A4 Expression Inhibits the Proliferation and Motility of Gallbladder Cancer Cells and Tumor Formation in Nude Mice

Fan

Bao

et al. 2021

CMAR

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Purpose Gallbladder cancer (GBC) is a common malignancy of the biliary tract and is characterized by rapid progression and early metastasis. Elucidating the molecular mechanisms of GBC could help to develop better treatment strategies. Materials and Methods Human GBC cell lines (GBC-SD and NOZ) were applied to determine the capacity of the proliferation and migration of cells using the MTT assay, colony formation, wound-healing assay as well as the Transwell™ assay. A nude xenograft was used to evaluate tumor growth in vivo. Results Using two types of GBC cell lines, we found that absence of solute carrier family (SLC) 39A4 (which encodes the zinc transporter ZRT/IRT-like protein [ZIP]4), could suppress the proliferation and migration of cells. Additionally, absence of ZIP4 could impair growth of xenografts in nude mice. While, over-expression of SLC39A4 could promote the GBC cell proliferation and migration, and inhibit apoptosis. We revealed that SLC39A4 might affect GBC progression by modulating the signaling pathways responsible for the survival, energy supply and metastasis of cells, and indicated that SLC39A4 could serve as a novel therapeutic target for GBC. Conclusion SLC39A4 promoted the viability and motility of GBC cells, and tumor formation in nude mice. We demonstrated an oncogenic potential for SLC39A4.

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“…mTOR expression is also enhanced in S. haematobium -associated bladder cancer, although this may be a general feature of malignancy rather than schistosomiasis (239). Recently, mTOR signaling in myeloid cells has also emerged as an attractive target for the treatment of hepatic fibrosis (240, 241).…”

Section: Common and Distinct Metabolic Features Of Tuberculosis Schimentioning

confidence: 99%

Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease

2019

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Metabolic reprogramming is rapidly gaining appreciation in the etiology of immune cell dysfunction in a variety of diseases. Tuberculosis, schistosomiasis, and sarcoidosis represent an important class of diseases characterized by the formation of granulomas, where macrophages are causatively implicated in disease pathogenesis. Recent studies support the incidence of macrophage metabolic reprogramming in granulomas of both infectious and non-infectious origin. These publications identify the mechanistic target of rapamycin (mTOR), as well as the major regulators of lipid metabolism and cellular energy balance, peroxisome proliferator receptor gamma (PPAR-γ) and adenosine monophosphate-activated protein kinase (AMPK), respectively, as key players in the pathological progression of granulomas. In this review, we present a comprehensive breakdown of emerging research on the link between macrophage cell metabolism and granulomas of different etiology, and how parallels can be drawn between different forms of granulomatous disease. In particular, we discuss the role of PPAR-γ signaling and lipid metabolism, which are currently the best-represented metabolic pathways in this context, and we highlight dysregulated lipid metabolism as a common denominator in granulomatous disease progression. This review therefore aims to highlight metabolic mechanisms of granuloma immune cell fate and open up research questions for the identification of potential therapeutic targets in the future.

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Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis

Cited by 33 publications

References 40 publications

SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis

SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis

Knockdown of SLC39A4 Expression Inhibits the Proliferation and Motility of Gallbladder Cancer Cells and Tumor Formation in Nude Mice

Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease

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