Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

Doodnauth, Sasha A.; Grinstein, Sergio; Maxson, Michelle E.

doi:10.1098/rstb.2018.0147

Cited by 62 publications

(58 citation statements)

References 105 publications

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“… 48 In addition, macropinocytosis has been described to be altered in differently polarized macrophages. 49 Both lipopolysaccharide and granulocyte-macrophage colony-stimulating factor were demonstrated to boost macropinosome formation, leading to increased uptake of fluids as well as soluble proteins. 50 We show here that macropinocytosis was indeed increased for 2 hours after stimulation with lipopolysaccharide+IFN-γ in our in vitro generated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets

Haider

Kral-Pointner

Mayer

et al. 2020

ATVB

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Objective: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden. Conclusions: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets

Haider

Kral-Pointner

Mayer

et al. 2020

ATVB

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“…Receptor-mediated stimulation of macropinocytosis is understood in outline form: it usually requires phosphatidylinositol 3 0 -kinase (PI3 K), other phospholipid-modifying enzymes and the small GTPases Rac, Ras and Rab5a. Constitutive macropinocytosis in macrophages also entails receptor-mediated signalling and PI3 K (see the article by Doodnauth et al [43]). However, the constitutive macropinocytosis of Dictyostelium and possibly also DC and Ras-transformed cancer cells use many of the same chemistries-PI3 K, Ras and Rac-but their regulation is independent of cell surface receptors.…”

Section: Macropinosome Formation and Maturationmentioning

confidence: 99%

The breadth of macropinocytosis research

Swanson

King

2018

Phil. Trans. R. Soc. B

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“…It is generally accepted that the main sources of accumulating lipids (mostly cholesterol and cholesteryl esters) in foam cells are atherogenic modified low-density lipoproteins (LDL). Arterial cells (macrophages, pericytes, and smooth muscle cells) take up these particles in an unregulated manner bypassing the specialized LDL receptor [3][4][5]. The mechanism of interaction of native (unmodified) LDL with a specific cell receptor is currently well known [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our Int.Int. J. Mol. Sci. 2020, 21, 2716 2 of 17 group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

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Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

Abstract: One contribution of 11 to a Theo Murphy meeting issue 'Macropinocytosis'.

Cited by 62 publications

References 105 publications

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets

The breadth of macropinocytosis research

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

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