Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors

He, Lizhi; Jhong, Jhih-Hua; Chen, Qi; Huang, Kai-Yao; Strittmatter, Karin; Kreuzer, Johannes; DeRan, Michael; Wu, Xu; Lee, Tzong-Yi; Slavov, Nikolai; Haas, Wilhelm; Marneros, Alexander G.

doi:10.1016/j.celrep.2021.109955

Cited by 157 publications

(111 citation statements)

References 109 publications

(173 reference statements)

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“…Upregulation of the expression of vitamin D receptor or that of VEGFA by retinoids during monocyte differentiation also indicates that retinoids promote the generation of such M2-type macrophages that participate in the regulation of tissue repair. Upregulation of TG2, or ALDH1a2 detected 48 h after retinoid addition also supports this view [ 59 ]. Interestingly, the involvement of Smad3 in mediating tissue repair responses of macrophages was just reported in an infarcted myocardium model [ 60 ].…”

Section: Discussionmentioning

confidence: 72%

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

Fige

Sarang

Sós

et al. 2022

Cells

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Clearance of apoptotic cells by bone marrow-derived macrophages differentiated from monocytes plays a central role in the resolution of inflammation, as the conversion of pro-inflammatory M1 macrophages to M2 macrophages that mediate the resolution process occurs during efferocytosis. Thus, proper efferocytosis is a prerequisite for proper resolution of inflammation, and failure in efferocytosis is associated with the development of chronic inflammatory diseases. Previous studies from our laboratory have shown that (13R)-all-trans-13,14-dihydroretinol (DHR), the product of retinol saturase, acting from day 4 of monocyte differentiation enhances the efferocytosis capacity of the resulted macrophages. Loss of retinol saturase in mice leads to impaired efferocytosis, and to development of autoimmunity. In the present paper, we report that in differentiating monocytes DHR, retinol, and all-trans retinoic acid all act directly on retinoic acid receptors and enhance the clearance of apoptotic cells by upregulating the expression of several efferocytosis-related genes. The effect of retinoids seems to be mediated by bone morphogenetic protein (BMP)-2, and the Smad3 transcription factor. In addition, retinoids also upregulate the expression of the vitamin D receptor and that of vascular endothelial growth factor A, indicating that altogether retinoids promote the generation of a pro-reparative M2 macrophage population during monocyte differentiation.

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Section: Discussionmentioning

confidence: 72%

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

Fige

Sarang

Sós

et al. 2022

Cells

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“…The ERK1/2 pathway is stimulated by different growth factors and acts downstream of the ras and raf oncogenes, playing a key role in proliferating cells. In addition, this signaling pathway has been shown to regulate immune responses in macrophages (43,62). In contrast, T3 inactivates the MAPK p38a.…”

Section: Discussionmentioning

confidence: 99%

Regulation of metabolic and transcriptional responses by the thyroid hormone in cellular models of murine macrophages

et al. 2022

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Oncogene-immortalized bone marrow-derived macrophages are considered to be a good model for the study of immune cell functions, but the factors required for their survival and proliferation are still unknown. Although the effect of the thyroid hormones on global metabolic and transcriptional responses in macrophages has not yet been examined, there is increasing evidence that they could modulate macrophage functions. We show here that the thyroid hormone T3 is an absolute requirement for the growth of immortal macrophages. The hormone regulates the activity of the main signaling pathways required for proliferation and anabolic processes, including the phosphorylation of ERK and p38 MAPKs, AKT, ribosomal S6 protein, AMPK and Sirtuin-1. T3 also alters the levels of metabolites controlling transcriptional and post-transcriptional actions in macrophages, and causes widespread transcriptomic changes, up-regulating genes needed for protein synthesis and cell proliferation, while down-regulating genes involved in immune responses and endocytosis, among others. This is not observed in primary bone marrow-derived macrophages, where only p38 and AMPK activation is regulated by T3 and in which the metabolic and transcriptomic effects of the hormone are much weaker. However, the response to IFN-γ is reduced by T3 similarly in immortalized macrophages and in the primary cells, confirming previous results showing that the thyroid hormones can antagonize JAK/STAT-mediated signaling. These results provide new perspectives on the relevant pathways involved in proliferation and survival of macrophage cell culture models and on the crosstalk between the thyroid hormones and the immune system.

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“…Moreover, Akt exists in three different isoforms and Akt1 and Akt2 can have opposing effects on macrophage polarization ( 60 ). The MEK/ERK1/2 pathway can also lead to opposing effects on macrophage polarization; it can be both a negative regulator of murine and human macrophage M2-type polarization ( 61 ) and an enhancer of M2-type polarization ( 62 ). While our experimental setting in vitro clearly reveals the pro-inflammatory action of C1QTNF3 as judged by the reduced proliferation of M0-type macrophages and the M1-polarizing effect, we also anticipate that the timing and the concentration of C1QTNF3, as well as the state and the type of the targeted macrophages, will determine whether C1QTNF3 primarily push M1- or M2-type polarization.…”

Section: Discussionmentioning

confidence: 99%

C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization

Micallef

Vujičić

et al. 2022

Front. Immunol.

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The adipose tissue undergoes substantial tissue remodeling during weight gain-induced expansion as well as in response to the mechanical and immunological stresses from a growing tumor. We identified the C1q/TNF-related protein family member C1qtnf3 as one of the most upregulated genes that encode secreted proteins in tumor-associated inguinal adipose tissue - especially in high fat diet-induced obese mice that displayed 3-fold larger tumors than their lean controls. Interestingly, inguinal adipose tissue C1qtnf3 was co-regulated with several macrophage markers and chemokines and was primarily expressed in fibroblasts while only low levels were detected in adipocytes and macrophages. Administration of C1QTNF3 neutralizing antibodies inhibited macrophage accumulation in tumor-associated inguinal adipose tissue while tumor growth was unaffected. In line with this finding, C1QTNF3 exerted chemotactic actions on both M1- and M2-polarized macrophages in vitro. Moreover, C1QTNF3 treatment of M2-type macrophages stimulated the ERK and Akt pathway associated with increased M1-like polarization as judged by increased expression of M1-macrophage markers, increased production of nitric oxide, reduced oxygen consumption and increased glycolysis. Based on these results, we propose that macrophages are recruited to adipose tissue sites with increased C1QTNF3 production. However, the impact of the immunomodulatory effects of C1QTNF3 in adipose tissue remodeling warrants future investigations.

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Global characterization of macrophage polarization mechanisms and identification of M2-type polarization inhibitors

Cited by 157 publications

References 109 publications

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

Regulation of metabolic and transcriptional responses by the thyroid hormone in cellular models of murine macrophages

C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization

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