Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis

Tao, Ran; Han, Meiwen; Yuan, Wei; Xiao, Fang; Huang, Jiaquan; Wang, Xiaojing; Luo, Xiaoping; Yan, Weiming; Wan, Xiaoyang; Ning, Qin

doi:10.1016/j.intimp.2022.109631

Cited by 6 publications

(5 citation statements)

References 55 publications

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“…Another recently published article demonstrated that Fgl2 may selectively localize to mitochondria, where it interacts with mitochondrial HSP90, thereby impeding the interaction between HSP90 and its target protein Akt. 45 Consequently, Fgl2 inhibits Akt phosphorylation and induces mitochondrial dysfunction in macrophages. Considering that FcγRIIB serves as a receptor for Fgl2, it is plausible to speculate that Fgl2 may bind to the surface of MDSCs through FcγRIIB.…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

Wu,

Liu,

Lei

et al. 2023

J Immunother Cancer

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BackgroundMyeloid-derived suppressor cells (MDSCs) are crucial mediators of tumor-associated immune suppression. Targeting the accumulation and activation of MDSCs has been recognized as a promising approach to enhance the effectiveness of immunotherapies for different types of cancer.MethodsThe MC38 and B16 tumor-bearing mouse models were established to investigate the role of Fgl2 during tumor progression. Fgl2 and FcγRIIB-deficient mice, adoptive cell transfer, RNA-sequencing and flow cytometry analysis were used to assess the role of Fgl2 on immunosuppressive activity and differentiation of MDSCs.ResultsHere, we show that fibrinogen-like protein 2 (Fgl2) regulates the differentiation and immunosuppressive functions of MDSCs. The absence of Fgl2 leads to an increase in antitumor CD8+T-cell responses and a decrease in granulocytic MDSC accumulation. The regulation mechanism involves Fgl2 modulating cholesterol metabolism, which promotes the accumulation of MDSCs and immunosuppression through the production of reactive oxygen species and activation of XBP1 signaling. Inhibition of Fgl2 or cholesterol metabolism in MDSCs reduces their immunosuppressive activity and enhances differentiation. Targeting Fgl2 could potentially enhance the therapeutic efficacy of anti-PD-1 antibody in immunotherapy.ConclusionThese results suggest that Fgl2 plays a role in promoting immune suppression by modulating cholesterol metabolism and targeting Fgl2 combined with PD-1 checkpoint blockade provides a promising therapeutic strategy for antitumor therapy.

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Section: Discussionmentioning

confidence: 99%

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

Wu,

Liu,

Lei

et al. 2023

J Immunother Cancer

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“…tissues of cirrhotic patients with underlying hepatitis C infection, promoted M1 polarization (124). Furthermore, autophagy triggered a M2-type, whereas LPS stimulation favored a M1-type macrophage polarization and blocked autophagy (125).…”

Section: The Role Of Macrophages In Fibrosis Initiation Progression A...mentioning

confidence: 96%

“…For example, complement factor C5a stimulates pro-inflammatory pathways via C5aR1 on macrophages, and C5aR1ko knockout mice showed a M1- to M2-type macrophage transition and reduced fibrosis in a MASH mouse model ( 122 ). HMBG1 secretion from injured hepatocytes induced NLRP3 inflammasome activation in macrophages ( 123 ), and fibrinogen-like protein 2 (Fgl2), which was upregulated in liver tissues of cirrhotic patients with underlying hepatitis C infection, promoted M1 polarization ( 124 ). Furthermore, autophagy triggered a M2-type, whereas LPS stimulation favored a M1-type macrophage polarization and blocked autophagy ( 125 ).…”

Section: The Role Of Macrophages In Fibrosis Initiation Progression A...mentioning

confidence: 99%

Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

Casari,

Siegl,

Deppermann

et al. 2023

Front. Immunol.

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During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible process, however, from the cirrhotic stage, there is significant progression to hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) and monocyte-derived macrophages are important drivers of fibrosis progression, but can also induce its regression once triggers of chronic inflammation are eliminated. In liver cancer, they are attracted to the tumor site to become tumor-associated macrophages (TAMs) polarized towards a M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis and hemostasis, platelets can also stimulate fibrosis and tumor development by secreting profibrogenic factors and regulating the innate immune response, e.g., by interacting with monocytes and macrophages. Here, we review recent literature on the role of macrophages and platelets and their interplay in liver fibrosis and hepatocellular carcinoma.

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“…It was reported that fibrinogen-like 2 (Fgl2) mediated mitochondrial damage, disrupted mitochondrial HSP90-Akt interactions. Moreover, Fgl2 induced M1 Polarization to secrete pro-inflammatory factors in hepatitis B ( 126 ). CXCL10 promoted M1 polarization, resulting in the activation of the JAK/STAT1 pathway ( 127 ).…”

Section: Liver Cirrhosis Immune Microenvironmentmentioning

confidence: 99%

“…On the contrary, the alternative M2 subtype secretes anti-inflammatory cytokines, which are stimulated by IL-4 or IL-13 (124). In the progression of NAFLD, it was found that hepatic macrophages polarized toward M2 and promoted HSC autophagy and activation by secreting prostaglandin E2 (PGE2) and then binding with EP4, which in turn favored the development of liver fibrosis and cirrhosis (125). It was reported that fibrinogen-like 2 (Fgl2) mediated mitochondrial damage, disrupted mitochondrial HSP90-Akt interactions.…”

Section: Macrophagementioning

confidence: 99%

Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells

Yang

Wang

et al. 2023

Front. Immunol.

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Cirrhosis is a progressive and diffuse liver disease characterized by liver tissue fibrosis and impaired liver function. This condition is brought about by several factors, including chronic hepatitis, hepatic steatosis, alcohol abuse, and other immunological injuries. The pathogenesis of liver cirrhosis is a complex process that involves the interaction of various immune cells and cytokines, which work together to create the hepatic homeostasis imbalance in the liver. Some studies have indicated that alterations in the immune microenvironment of liver cirrhosis are closely linked to the development and prognosis of the disease. The noteworthy function of mesenchymal stem cells and their paracrine secretion lies in their ability to promote the production of cytokines, which in turn enhance the self-repairing capabilities of tissues. The objective of this review is to provide a summary of the alterations in liver homeostasis and to discuss intercellular communication within the organ. Recent research on MSCs is yielding a blueprint for cell typing and biomarker immunoregulation. Hopefully, as MSCs researches continue to progress, novel therapeutic approaches will emerge to address cirrhosis.

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Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis

Cited by 6 publications

References 55 publications

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

Fibrinogen-like protein 2 promotes tumor immune suppression by regulating cholesterol metabolism in myeloid-derived suppressor cells

Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells

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