Extracellular acidosis modulates the endocytosis and maturation of macrophages

Kong, Xiaoling; Tang, Xiang D.; Du, Wenjiao; Tong, Jing; Yan, Yutao; Zheng, Fang; Fang, Min; Gong, Feili; Tan, Zheng

doi:10.1016/j.cellimm.2012.12.009

Cited by 44 publications

(45 citation statements)

References 29 publications

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“…[19][20][21] An acidic extracellular environment has also been described to modulate endocytosis/phagocytosis in macrophages. [22][23][24] On the other hand, studies revealed that the chemical structure of polymers may also play a role for their endocytotic uptake. Liu et al 25 demonstrated that HPMA-based polymers containing alkaline side chains, eg, 2-(N,N-dimethylamino) ethyl methacrylate (positive ζ potential), were taken up by cells much stronger than polymers containing acidic adducts, eg, methacrylic acid (negative ζ potential).…”

Section: Introductionmentioning

confidence: 99%

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

Gündel¹,

Allmeroth²,

Reime³

et al. 2017

IJN

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Background Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. Materials and methods Six different N -(2-hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO 2 ≈1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. Results The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin-dependent endocytosis. Conclusion The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO 2 ) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient.

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Section: Introductionmentioning

confidence: 99%

Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia

Gündel¹,

Allmeroth²,

Reime³

et al. 2017

IJN

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“…31 We showed that 2 atherosclerosis-associated activators of the NLRP3 inflammasome, cholesterol crystals and extracellular acidosis, caused downregulation of CIITA and class II HLA molecules in HMDMs after 16 to 24 hours of stimulation. An earlier report showed modest upregulation of class II HLA after 3-hour incubation of mouse macrophages in acidic environment, 32 but it is likely that the short time window used did not allow CIITA protein turnover and clearance from class II HLA promoters to occur. Notably, the observed inhibitory effect of cholesterol crystals on CIITA expression may be related to p38 MAPK activation, which has been found to attenuate CIITA and class II HLA expression at least in mouse macrophages.…”

Section: Limitations Of the Studymentioning

confidence: 94%

p38δ MAPK

Rajamäki

Mäyränpää

Risco

et al. 2016

ATVB

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Objective— Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions. Approach and Results— Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway–focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18. Immunohistochemical stainings of the advanced plaques revealed macrophage foam cells positive for NLRP3 inflammasome components around the necrotic lipid cores. The polymerase chain reaction array target p38δ mitogen-activated protein kinase was upregulated in advanced plaques and strongly expressed by lesional macrophage foam cells. In cultured human monocyte–derived macrophages, the p38δ mitogen-activated protein kinase was activated by intracellular stress signals triggered during ATP- and cholesterol crystal–induced NLRP3 inflammasome activation and was required for NLRP3-mediated IL-1β secretion. Conclusions— Increased expression of the key inflammasome components in advanced coronary lesions implies enhanced activity of the inflammasome pathway in progression of coronary atherosclerosis. The p38δ mitogen-activated protein kinase was identified as a novel regulator of NLRP3 inflammasome activation in primary human macrophages, and thus, represents a potential target for modulation of atherosclerotic inflammation.

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“…Thus, when macrophages are incubated with high LDL concentrations comparable to those found the intimal interstitial fl uid ( 128 ), foam cells are formed as a result of fl uid phase pinocytosis of unmodifi ed LDL particles ( 129 ). Fluid phase pinocytosis by macrophages has been reported to be increased at acidic pH ( 19,20 ). Thus, most of the proposed mechanisms involved in the uptake of lipoproteins by macrophages and foam cell formation are augmented at acidic extracellular pH ( Fig.…”

Section: Acidity Increases Ldl Uptake By Macrophagesmentioning

confidence: 94%

“…In a recent study, expression of the phosphatidylserine receptor, stabilin-1, on macrophages was shown to be increased at pH 6.8, resulting in enhanced clearance of apoptotic cells ( 40 ). Finally, extracellular acidosis enhanced fl uid phase endocytosis by macrophages and dendritic cells, accompanied by increased expression of molecules involved in antigen presentation, including major histocompatibility complex I and CD86 ( 19,20 ).…”

Section: Downloaded Frommentioning

confidence: 98%

“…Thus, macrophages, the most abundant immune cells in atherosclerotic lesions, will remain viable despite the acidic microenvironment of the atherosclerotic intima and are subject to acidosis-induced a key bactericidal response, the oxidative burst ( 16,17 ). Acidosis greatly enhances the receptor-mediated uptake of opsonized bacteria into macrophages thereby promoting effi cient clearance of an infection ( 18 ), and it also boosts antigen presentation by these cells via enhancing fl uidphase endocytosis and increasing the expression of molecules involved in antigen presentation ( 19,20 ). Extracellular acidity is also needed for the hydrolytic activity of lysosomal enzymes secreted by the phagocytes, and thereby tends to augment the extracellular destruction of bacteria.…”

Section: Effect Of Local Acidosis On Immune Functions Of Macrophagesmentioning

confidence: 99%

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