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

EGCG [109, 205]

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

6-Gingerol [74, 75]

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)

Baicalin [23, 207,208,209]

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;

Berberine [122, 123]

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

Quercetin [172, 173, 213]

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

Curcumin [113,114,115, 136,137,138,139]

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

  1. MerTK Mer proto-oncogene tyrosine kinase, KLF4 Krüppel-like factor 4, LPS Lipopolysaccharide, PAI-2 Plasminogen activator inhibitor 2, ALI acute lung injury, IBD Inflammatory bowel disease, H2O2 Hydrogen peroxide, ROS Reactive oxygen species, Ox-LDL Oxidized low-density lipoprotein, LPC Lysophosphatidylcholine, Nrf2 Nuclear factor E2-related factor 2, HO-1 Heme oxygenase-1, CO Carbon monoxide,Mabs Macrophages infected with Mycobacterium abscessus, NK cells natural killer cells, MPMs Murine peritoneal macrophages, EGCG Epigallocatechin gallate, SFN Sulforaphane, PCA Protocatechuic acid, BMDCs Bone marrow-derived dendritic cells, cDC1s Conventional type 1 dendritic cells, TIPE2 Tumor necrosis factor alpha-induced protein 8-like 2, TRPV1 Transient receptor potential vanilloid 1, ICAM-1 Intercellular adhesion molecule-1, Sirt1 Sirtuin 1, MCP-1 Monocyte chemoattractant protein-1, DPPH 2,2-Diphenyl-1-picrylhydrazyl, ACs Apoptotic cells, IBD Inflammatory bowel disease, FAF1 Fas-associated factor 1, ALI Acute lung injury, Keap1 Kelch-like ECH-associated protein 1, HDL-C High-density lipoprotein cholesterol, SMMHC Smooth muscle myosin heavy chain, ERK Extracellular signal-regulated kinase, NO Nitric oxide, Nrf2 Nuclear factor-erythroid 2-related factor 2, HO-1 Heme oxygenase-1, ABCA1 ATP-binding cassette transporter A1, SR-A Scavenger receptor, HASMCs Human aortic smooth muscle cells.