The Effect of Cigarette Smoke Exposure on Efferocytosis in Chronic Obstructive Pulmonary Disease; Molecular Mechanisms and Treatment Opportunities

Figures & data

Figure 1. The main efferocytosis signaling and steps. These signals are related to the apoptotic cells (ACs), characterizing by ‘Find-Me’ signals and also the absence of ‘Don’t Eat-Me’ signals. ‘Don’t Eat-Me’ signals, such as CD47 and CD31 commonly found on living cells. However, there are major steps in efferocytosis including: (1): ‘Find-Me’ signals (to attract phagocytes to sites of apoptotic cell death), (2): ‘Eat-Me’ signal (to catch ACs), and (3): the processes of engulfment and digestion. Ultimately, effective efferocytosis results in 4): the production of anti-inflammatory cytokines, such as IL-10 and TGF-β. Moreover, an additional steps include ‘Keep-Out’ signal helps to efferocytosis to reduce number of unwanted neutrophils. On the other hand, defective efferocytosis can lead to necrosis, which in turn increases inflammation and inflammatory diseases, such as COPD. In this line, cigarette smoke can impair efferocytosis activity, which leads to necrosis and tissue inflammation.

Figure 2. Effective and defective efferocytosis signaling. A: Effective efferocytosis in the physiologic condition that is regulated by certain pathways/factors; B: Defective efferocytosis in pathophysiological conditions caused by cigarette smoking. Abbreviations: BAI-1: Brain-specific angiogenesis factor 1; C1q: Complement component 1q; CD36: Cluster of differentiation 36; FCRγ: Fc receptor γ-chain; Gas6: Growth Arrest Specific 6; IL-10: Interleukin 10; LPC: Lysophosphatidylcholine; MerTK: Mer tyrosine kinase; MGF-E8: Milk fat globule‑EGF factor 8; NTP: Nucleoside triphosphate; PGE2: Prostaglandin E₂; PPAR: Peroxisome proliferator activated receptor; PtdSer: Phosphatidylserine; S1P: Sphingosine 1-phosphate; TGF-β: Transforming growth factor beta; TIM-1: T-cell immunoglobulin and mucin domain 1; TyrRS: Tyrosyl-tRNA synthetase.

Table 1. The main efferocytosis related-molecules.

Cells	Live cells & Phagocytes	ACs& Neutrophils	ACs& Phagocytes
Steps	‘Don’t Find me’ signals	‘Keep out’ signals	Pre-Engulfment		Post-Engulfment
			‘Find me’ signals	‘Eat me’ signals	Engulfment	Processing	Anti-inflammatory & Self-tolerance responses
Molecules	CD47, CD31	Lactoferrin Annexin A1 dRP S19	ATP/UTP S1P LPC sIL-6R FKN/CX3CL1 dRP S19 EMAP II Annexin A1 TryRS	PtdSer Calreticulin Protein S MFG-E8 MerTK Gas6 TSP-1 C1q/C4	RhoA Rac CDC42 ABCA7 Stabilin-2 BAI-1 TIMs	Rab5 Rab7	IL-10 TGF-β PGE2

Abbreviated list: ABCA7: ATP-binding cassette transporter A7; BAI-1: Brain-specific angiogenesis inhibitor 1; CDC42: Cell division control protein 42; EMAP II: Endothelial monocyte activating polypeptide II; FKN: Fractalkine/CX3CL1; IL-10: Interleukin 10; LPC: Lysophosphatidylcholine; MerTK: Mer tyrosine kinase; MFG-E8: Milk fat globule-EGF factor 8; PGE2: Prostaglandin E2; PtdSer: Phosphatidylserine; dRP S19: dimer of ribosomal protein S19; S1P: Spingosine-1-phosphate; sIL-6R: Soluble IL-6 receptor; TSP-1: Thrombospondin-1; TGF-β: Transforming growth factor beta; TIMs: T-cell immunoglobulin mucins; TryRS: Tyrosyl tRNA synthetase.

Table 2. The main defective efferocytosis-related factors/pathways that are affected by CS in COPD.

Factors/Pathways	Effect on efferocytosis	COPD	Ref
®Sphingosine-1-phosphate (S1P)	®	↑	[54,55]
®Zrt-/Irt-like protein proteins (ZIPs)	®	↑	[56]
↑Endothelial microparticles (EMPs)	®	↑	[57]
↑ Endoplasmic reticulum stress and Oxidative stress	®	↑	[58–60]
↑ Neutrophilic inflammation	®	↑	[61]
®Formyl peptide receptor 2/3	®	↑	[39]

Table 3. The regents that have the potential therapeutic effect for treating CS-related lung injury.

Regents/Drugs	Molecular Formula	Mechanism
Recombinant GM-CSF [31]	C73H129N27O24	Increasing the expression of CD16/32 on AMs. Increasing uptake and efferocytosis of ACs by AMs. Increasing expression of Rab5 and Rab7.
Thiazolidinediones (rosiglitazone & pioglitazone) [117, 118]	C18H19N3O3S	Preventing the effect of CS on PPAR-γ.
	C19H20N2O3S
Aminophylline /theophylline [26, 55]	C16H24N10O4	Restoring effective efferocytosis by inhibiting of Trichostatin A, which suppresses the activity of Rac.
	C7H8N4O2
Statins [119] (Lovastatin, simvastatin)	Different types	Decreasing the incidence of COPD exacerbations. Preventing the development of emphysema. Blocking the RhoA–Rho kinase pathway. Increasing efferocytosis. Decreasing production of MMP-1, MMP-2 and MMP-9. Reducing oxidant generation, and prevent emphysema formation.
Cyclosporin A [120]	C62H111N11O12	Preventing neutrophil infiltration and airspace enlargement.
Alpha-1 antitrypsin (A1AT) [44]	C79H130N22O26	Improving AM engulfment via inhibiting of TNF-α converting enzyme activity. Decreasing mannose receptor shedding. Increasing efferocytosis receptors, such as mannose- and PtdSer receptors.
Resolvin D1 [121]	C22H32O5	Reducing neutrophilic lung inflammation as well as pro-inflammatory cytokine production. Increasing differentiation of M2 macrophages. Upregulating IL-10. Increasing neutrophil efferocytosis.
Thymoquinone [63]	C10H12O2	Enhancing efferocytosis. Antagonizing the effects of CSE on S1PR5 and efferocytosis. Protecting bronchial epithelial cells from CS-induced apoptosis.
FTY720 phosphate (fingolimod phosphate) [36]	C19H34NO5P	Reducing CS‐induced clumping of SK1/2. Increasing efferocytosis.
Azacytidine [51]	C8H12N4O5	Increasing efferocytosis in macrophages by DNA de-methylation of S1PR5. Rescuing the cells from the CS-induced defect in efferocytosis.
Azithromycin [122]	C38H72N2O12	Improving alveolar macrophage phagocytic ability. Reducing bronchial epithelial cell apoptosis. Increasing mannose receptor. Reducing inflammatory markers.
Amitriptyline [123, 124]	C20H23N	Inhibiting sphingoymelinase. Increasing efferocytosis by AMs.
GSK484 [70]	C27H31N5O3	Restoring efferocytosis ability of cadmium-treated macrophages.
Tauroursodeoxycholic acid and GSK2606414 [56]	C26H45NO6S	Restoring the efferocytosis. Reversing The CSE-induced ROCK activity.
	C24H20F3N5O
Procysteine [55]	C4H5NO3S	Increasing glutathione. Improving efferocytic function of AMs.
Tocotrienols [82]	C26H38O2	Inhibiting NFκB activation. Decrease cytokine secretion and M1 accumulation.

ACs: Apoptotic cells; AMs: Alveolar macrophages; COPD: Chronic obstructive pulmonary isease; CSE: Cigarette smoke extract; GM-CSF: Granulocyte–macrophage colony-stimulating factor; HDAC2: Histone deacetylase 2; IL: Interleukin; MMPs: Matrix metalloproteinases; PPAR-γ: Peroxisome proliferator-activated receptor γ; PtdSer: Phosphatidylserine; S1PR5: Sphingosine-1-Phosphate Receptor 5.

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Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.