Macrophage polarization and function: new prospects for fibrotic disease

Zhou, Dexi; Yang, Kui; Chen, Lu; Wang, Yaqin; Zhang, Wen; Xu, Zhenyu; Zuo, Jian; Jiang, Hui; Luan, Jiajie

doi:10.1038/icb.2017.64

Cited by 23 publications

(17 citation statements)

References 63 publications

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“…The most studied gene from Egr family is Egr1, while the function of Egr2 is less studied ( 47 , 48 ). There are several conditions such as fibrotic process and hypoxia that affect in vivo ( 49 , 50 ). Therefore it is important to know the level of Egr2 expression in macrophages in such conditions.…”

Section: Discussionmentioning

confidence: 99%

Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ

et al. 2018

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The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse in vitro and in vivo models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.

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Section: Discussionmentioning

confidence: 99%

Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ

et al. 2018

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“…Indeed, MΦ can adopt distinct phenotypes and activation states depending on the nature of the surrounding environmental signals. Macrophagic polarization states are commonly divided into two categories: the proinflammatory “classically activated MΦ” or M1 type and the “alternative activated MΦ” or M2 types . Polarization can impact the expression of cell surface receptors and is also supposed to modulate efferocytosis .…”

Section: Resultsmentioning

confidence: 99%

“…Macrophagic polarization states are commonly divided into two categories: the proinflammatory "classically activated MΦ" or M1 type and the "alternative activated MΦ" or M2 types. 21 Polarization can impact the expression of cell surface receptors and is also supposed to modulate efferocytosis. 12 Moreover, polarization of MΦ is also disrupted in SSc.…”

Section: Comparison Of Efferocytosis Capacities Of Monocytederived Mamentioning

confidence: 99%

Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

et al. 2018

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A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of autoimmunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte‐derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 ± 3.0; n = 21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 ± 3.0; n = 31; P < 0.001). In comparison with HD, SSc MDM exhibited a downregulated expression of scavenger receptor (SR)‐B1, SR‐A1 and integrin β5 (ITGβ5). In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of ITGβ5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder.

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“…Biliary obstruction and abnormal bile formation result in the accumulation of bile acids, which causes progressive bile duct destruction and hepatic inflammation, and further contributes to fibrosis, cirrhosis, and eventually liver failure [35][36][37]. It has been well documented that hepatic inflammation is an essential driving force for liver fibrosis by recruiting inflammatory cells and activating HSCs [33,38]. Pro-inflammatory cytokines repress the expression and function of hepatocellular transporters and further result in cholestatic hepatitis [35].…”

Section: Discussionmentioning

confidence: 99%

“…It is now well recognized that besides liver-resident macrophages, blood circulating BMDMs are also a vital source of hepatic macrophages and play a critical role in tissue repair and inflammatory responses [18,32]. BMDMs can transdifferentiate into either pro-inflammatory phenotype M1 or anti-inflammatory phenotype M2 macrophages in response to different stimuli, e.g., LPS and interferon-γ for M1 or IL-4 and IL-13 for M2 [15,33]. To determine the role of exosomal H19 in the activation and differentiation of BMDMs, we first examined the effect of H19Exo on M1 and M2 stimulator-induced polarization of WT and H19KO BMDMs.…”

Section: Effects Of Cholangiocyte-derived Exosomal H19 On Bmdm Activamentioning

confidence: 99%

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

Liu

Wang

et al. 2020

Cells

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Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C–C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases.

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Macrophage polarization and function: new prospects for fibrotic disease

Cited by 23 publications

References 63 publications

Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ

Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPβ

Efferocytosis capacities of blood monocyte‐derived macrophages in systemic sclerosis

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

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