Table 2 The effect of phytochemicals on efferocytosis and autophagy.
From: Phytochemical-mediated efferocytosis and autophagy in inflammation control
Phytochemical | Sources | Effects on Efferocytosis & inflammation resolution | Related to efferocytosis | Conditions | Tested models |
---|---|---|---|---|---|
Camellia sinensis (Green tea) | -Attenuates inflammatory response by targeting Notch signaling pathway -Knockdown of Notch 1/2 expression impairs the downregulation of inflammatory response by EGCG -Inhibits LPS-induced inflammation & turns off Notch signaling -Enhances phagocytosis of macrophages & populations of T- & B-cells & NK cell activity. | -The inhibition of the Notch 1 & Notch 2 attenuates inflammation. -Notch signal regulates macrophage phagocytosis of tumor cells by SIRPα. | Inflammation, Leukemia | -Human macrophages, -Leukemic BALB/c mice | |
Zingiber officinale (Ginger) | -Reduces cerebral infarct volume, improves brain edema & neurological scores, & reverses brain histomorphological damage. -Reduces NLRP3 inflammasome-derived inflammation & neuronal apoptosis, & upregulates autophagy. -Has protective effects against 6-hydroxydopamine-induced apoptosis. | Autophagy & efferocytosis are interconnected processes, where autophagy boosts the ability to perform efferocytosis, & efferocytosis influences autophagic pathways. | Cerebral ischemia/reperfusion injury | -Adult male Sprague-Dawley rats | |
Apigenin [206] | Petroselinum crispum (Parsley), Matricaria chamomilla (Chamomile), Apium graveolens (Celery), Citrus × sinensis (Orange) | -Induces apoptosis of Ox-LDL-loaded macrophages -Reduces PAI-2 expression -Suppresses phosphorylation of AKT at Ser473 -Executes anti-atherogenic effects by inducing macrophage apoptosis | -Uptake of Ox-LDL by macrophages can impair their efferocytic function, as Ox-LDL can contribute to cellular stress & dysfunction. -Increased expression of PAI-2 in Ox-LDL-loaded macrophages may be a protective response to maintain their efferocytic capabilities. -PAI-2 inhibits proteases involved in the breakdown of extracellular matrix, which is important for the efficient engulfment of ACs during efferocytosis. -AKT signaling enhances macrophage survival & efferocytosis by supporting cytoskeletal rearrangements & phagocytosis of ACs. | Atherogenesis | ApoE-/- mice (in vivo) Ox-LDL-loaded MPMs (in vitro) |
Scutellaria baicalensis (Baikal skullcap) | -Inhibits the activation of the CX3CL1-CX3CR1 axis & NF-κB pathway. -Induces M2C macrophage polarization, enhancing phagocytosis & efferocytosis. -Impairs Th1 polarization by inhibiting DC maturation & suppressing the expression of pro-inflammatory molecules. -Alleviates IBD by limiting M1 macrophage polarization, & promoting anti-inflammatory cytokine expression. | -The CX3CL1-CX3CR1 axis is involved in inflammation, & its inhibition, along with the NF-κB pathway, can suppress pro-inflammatory signaling. -Polarization towards the M2C phenotype enhances the phagocytic & efferocytic functions of macrophages. -Impairs Th1 polarization by inhibiting DC maturation & suppressing pro-inflammatory molecule expression. -Th1 cells promote pro-inflammatory responses. | -ALI; -IBD; -DCs-related acute & chronic diseases. | -LPS-induced ALI in mice CX3CL1-knockout (CX3CL1-KO or CX3CL1-/-) mice; - MPMs, -Mice with DSS-induced colitis; | |
Hydrastis canadensis (Goldenseal), Berberis vulgaris (Barberry), Coptis chinensis (Chinese goldthread) | -Reduces ox-LDL-induced inflammation in a dose- & time-dependent manner. -Increases the ratio of LC3II/LC3I & SQSTM1/p62, which are markers of autophagy activation. -Increases the ratio of the activated form of AMPK & decreases the ratio of activated form of mTOR. | - Ox-LDL can trigger inflammation, impairing efferocytosis. -An increased LC3II/LC3I & SQSTM1/p62 ratio indicates enhanced autophagy activation, engulfment & degradation of ACs & promoting efferocytosis. -The increased ratio of activated AMPK & decreased ratio of activated mTOR indicate a shift towards a pro-autophagy state, enhancing the autophagic machinery & efferocytosis. | - Atherosclerosis, inflammation induced by ox-LDL; -Bacterial infection | -J774A.1 cells; -Murine macrophages | |
Crocin [210] | Crocus sativus (Saffron) | -Elevates M1 activity indicators in uncommitted macrophages -Prevents the increase in M1 indicators when co-treated with LPS + IFN-γ -Increases M1 induction when pretreated before the addition of LPS + IFN-γ -IL-10 was not detectable in any experimental groups | - Preventing the increase in M1 indicators with LPS + IFN-γ co-treatment, may support a more anti-inflammatory environment conducive to efferocytosis. -The absence of IL-10 suggests weak anti-inflammatory signaling, which may impede inflammation resolution & the clearance of ACs. | M1/M2 macrophage imbalance, inflammation | J774A.1 macrophages |
Hydroalcoholic Fruit Extract of Solanum diploconos (Mart.) Bohs [211] | Fruit of the Solanum diploconos (Holy blackberry) | -Impairs neutrophil chemotaxis & cytokine production/release -Increases efferocytosis of apoptotic neutrophils by macrophages -Modulates inflammatory mediator release -Promotes fibroblast proliferation & skin wound healing -Shows no signs of toxicity or genotoxicity | Impairing neutrophil chemotaxis & cytokine production can reduce excessive inflammation, fostering a more anti-inflammatory environment that supports efferocytosis.-Enhancing the efferocytosis of apoptotic neutrophils by macrophages can promote the efficient clearance of these inflammatory cells. | Inflammation, skin wound healing | In vitro (neutrophils, macrophages), in vivo (animal model) |
Pomegranate Peel extract [212] | Allium cepa (Onion), Malus domestica (Apple), Vitis vinifera (Grape), Vaccinium spp. (Berries) | -Decreases plaque necrosis & increases lesional collagen content. -Improves plaque stability. -Favorable changes in metabolic parameters, (e.g., lower blood glucose, cholesterol, & triglyceride levels) -Enhances efferocytosis efficiency, through the efferocytosis receptor Mertk & blocking the shedding of Mertk. | By improving plaque stability, modulating metabolic parameters, enhancing macrophage efferocytosis via Mertk upregulation, & preserving Mertk function by blocking its shedding, these factors collectively support efficient clearance of ACs. | Atherosclerosis; advanced atherosclerosis progression | -Apoe-/- mice; In vitro |
Allium cepa (Onion), Malus domestica (Apple), Vitis vinifera (Grape), Vaccinium spp. (Berries) | -Inhibits monocyte migration -Decreases the expression of ICAM-1 & MCP-1 -Increases cholesterol efflux -Prevents cell infiltration in atherosclerotic plaques -Reduces the risk of stroke or brain destruction by mediating the LXR/RXR signaling pathway. -Promotes M2 polarization. | -Inhibiting monocyte migration, creating a more favorable environment for efferocytosis. -Downregulating ICAM-1 & MCP-1, which recruit inflammatory cells, can promote an anti-inflammatory state that supports efferocytosis. -The LXR/RXR signaling pathway is involved in the regulation of inflammatory processes & lipid metabolism. -Promoting M2 polarization enhances macrophage efferocytic capacity & inflammation resolution. | Atherosclerosis, inflammation; - Osteoarthritis, chronic synovitis | -THP-1 macrophages; - In vivo (animal model) | |
Rubus imperialis extract & niga-ichigoside F1 compound [214] | Leaves of the Rubus imperialis plant; Fruit of Rubus coreanus Leaves of Rubus imperialis, Rubus coreanus (Fruit) | -Promotes reduction in the inflammatory process induced by LPS or carrageenan. -Reinforces NO reduction in LPS-stimulated neutrophils. -Increases efferocytosis. -Shows wound healing properties. -Exhibits scavenging activity for DPPH -Provides cytoprotection in H2O2-induced oxidative stress. -Niga-ichigoside F1 reduces NO secretion. | -Reducing NO production in LPS-stimulated neutrophils can help dampen the inflammatory response & support the resolution of inflammation & efferocytosis. - DPPH scavenging indicates antioxidant properties that help mitigate oxidative stress, creating a favorable environment for efferocytosis. - H2O2 induces oxidative stress, which impairs cellular function (e.g., efferocytosis). | Wound healing, inflammation | In vivo (mice), in vitro (L929 cells, neutrophils) |
SFN [215] | Brassica oleracea (Broccoli), Brassica rapa (Chinese cabbage), Brassica napus (Kale) | -Decreased mycobacterial burden. -Activates efferocytosis. -Activation of efferocytosis was found to be caspase 3/7 independent but dependent on p38 MAPK signaling. -The induction of p38 MAPK is linked to the Nrf2 signaling pathway. | The activation of the p38 MAPK pathway, which regulates efferocytosis, is also linked to the Nrf2 signaling pathway. The connection between p38 MAPK & Nrf2 signaling indicates that modulating this pathway affects the efficiency of efferocytosis. | Mycobacterium abscessus (Mabs) | Human THP-1-derived macrophages |
PCA [216] | Olea europaea (olives), Hibiscus sabdariffa (roselle), Eucommia ulmoides (du-zhong), Citrus microcarpa Bunge (calamondin), & Vitis vinifera (white wine grapes) | -Increases the continual efferocytic capacity of macrophages -Inhibits the progression of advanced atherosclerosis -Reduces intracellular amounts of miR-10b -Promotes miR-10b secretion in extracellular vesicles -Increases abundance of the miR-10b target KLF4 -Transcriptionally induces the gene encoding MerTK -Increases continual efferocytic capacity | -Reducing the intracellular levels of miR-10b enhances efferocytosis through the modulation of downstream target genes (e.g., KLF4). -MerTK is a key receptor involved in the recognition & engulfment of ACs during efferocytosis. The transcriptional induction of the MerTK gene can increase the expression of this efferocytosis receptor. | Advanced atherosclerosis | Mice, naive macrophages |
Ginsenoside Rg5 [217] | Panax ginseng, Panax quinquefolius (Ginseng) | - Promotes wound healing. - Reduces the negative regulation of SLC7A11 on the efferocytosis of DCs. - Physically interacts with SLC7A11 & suppresses its activity. - Reduces NF-κB p65 & SLC7A11 expression in the wounded areas. - Reduces glycose storage & enhances anaerobic glycolysis in DCs. | -By reducing the negative regulation of SLC7A11 on DCefferocytosis, these factors can promote the efficient clearance of ACs by DCs. - The reduction in NF-κB p65 & SLC7A11 expression in the wounded areas suggests a potential anti-inflammatory & pro-efferocytosis effect. | Diabetic wounds | Mice, BMDCs, cDC1s |
Celosins [120] | The active constituents extracted from Celosia argentea (Cockscomb). | - Reduced the prevalence of plaque in the aorta. - Promoted autophagy. - Reduced phagocytosis of macrophages & the formation rate of foam cells. -Down-regulates the expression of CD36 & SR-A1 genes. -Up-regulates the expression of ABCA1 & ABCG1 genes. -Increased the levels of autophagy-specific proteins LC3 & beclin 1. | - Excessive lipid phagocytosis by macrophages can lead to foam cell formation, impairing efferocytosis. -CD36 & SR-A1 are receptors that mediate the uptake of lipids, including Ox-LDL. -ABCA1 & ABCG1 are transporters involved in the efflux of cholesterol from cells. | Atherosclerosis | ApoE-/-mice, Foam cell model using peritoneal macrophages |
Low concentration resveratrol [76] | Vitis vinifera (Grape), Arachis hypogaea (Peanut), Vaccinium spp. (Berries) | -Sirt1 & autophagy marker proteins were increased & decreased in the low & high nicotinamide groups. -Efferocytosis was highest in the resveratrol group & relatively lower in the low & high concentration nicotinamide groups. -Enhancing Sirt1-mediated autophagy improves the efferocytosis. | -Increase the levels of Sirt1 & autophagy-related proteins (such as LC3 & beclin-1), resulting in enhanced efferocytosis of ACs. | Atherosclerosis | RAW264.7 cells |
Tnnin with honey [218] | Citrus limon fruit juice | -Shows antilipidemic & antioxidant activity. -Inhibits LDL oxidation, preventing foam cell development. -Inhibits proliferation & induced apoptosis. | Increasing OxLDL reduces eferocytosis by the formation of macrophage foam cells. | Atherosclerosis | RAW 264.7 & THP-1 cells |
An extract of Scoparia dulcis [219] | Scoparia dulcis | -Shows potent antioxidant activity & scavenged H2O2. -Improves erythrocyte membrane stabilization. -Inhibits lipid peroxidation & LDL oxidation, preventing foam cell formation. | - Oxidative stress & the accumulation of ROS, such as H2O2, can impair cellular function & efferocytosis. - Erythrocytes can release signals that promote the clearance of ACs through efferocytosis. | Atherosclerosis | RAW 264.7 cells |
Millet shell polyphenols [220] | Millet shell | -Inhibits lipid phagocytosis, reducing the formation of macrophage-derived foam cells. -Reduces the secretion of IL-1β & TNF-α by inhibiting STAT3 & NF-κB expression. -Promotes the transformation of HASMCs from synthesis to contraction, reducing the formation of SMC-derived foam cells. -Regulates the gene expression levels of SMMHC, desmin, smoothelin, & elastin. -Increased HDL-C. | -The inhibition of STAT3 & NF-κB in macrophages is a key mechanism, which can enhance efferocytosis. By reducing the secretion of IL-1β & TNF-α, a more favorable environment is established for the effective clearance of ACs by macrophages. | Atherosclerosis | Macrophages & HASMCs (cell lines), ApoE-/- mice |
Tanshinone IIA [221] | Salvia miltiorrhiza Bunge (Danshen) | -Reduces macrophage content, cholesterol accumulation, & atherosclerotic plaque development. -Inhibits foam cell formation induced by ox-LDL by reducing ox-LDL uptake & promoting cholesterol efflux. -Reduces the expression of SR-A & increases the expression of ABCA1 & ABCG1. -Activates of the ERK/ Nrf2/ HO-1 pathway. | - SR-A facilitates the uptake of modified lipoproteins, leading to foam cell formation. - ABCA1 & ABCG1 are cholesterol transporters that promote cholesterol efflux from cells, preventing excessive lipid accumulation. -The ERK signaling pathway regulates transcription factors like Nrf2, which is a master regulator of antioxidant & cytoprotective genes, including HO-1. -The activation of the ERK/Nrf2/HO-1 pathway likely underlies how these factors modulate genes involved in lipid metabolism and efferocytosis. | Atherosclerosis | Human macrophages, ApoE-/- mice |
The rhizomes of the turmeric plant (Curcuma longa) | -Exhibits anti-inflammatory effects. -Has inhibitory effects on the activation of the NLRP3 inflammasome in macrophages. -Increases M2 phenotype & reduces lipid accumulation induced by Ox-LDL. -Modulates the microglial transcriptome, activates the Akt/Nrf2 pathway, & exhibits neuroprotective effects through Sirt1 signaling. | - The inhibition of the NLRP3 inflammasome, increasing anti-inflammatory M2 phenotype, the reduction in lipid accumulation, & the modulation of microglial function, contributing to creating a more favorable cellular environment for efficient efferocytosis. | Inflammatory conditions | C57BL/6 mice, MCAO rats, rat cerebral cortical neurons, THP-1 monocytes/macrophages |