Comprehensive view of macrophage autophagy and its application in cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) are the primary drivers of the growing public health epidemic and the leading cause of premature mortality and economic burden worldwide. With decades of research, CVDs have been proven to be associated with the dysregulation of the inflammatory response, with macrophages playing imperative roles in influencing the prognosis of CVDs. Autophagy is a conserved pathway that maintains cellular functions. Emerging evidence has revealed an intrinsic connection between autophagy and macrophage functions. This review focuses on the role and underlying mechanisms of autophagy-mediated regulation of macrophage plasticity in polarization, inflammasome activation, cytokine secretion, metabolism, phagocytosis, and the number of macrophages. In addition, autophagy has been shown to connect macrophages and heart cells. It is attributed to specific substrate degradation or signalling pathway activation by autophagy-related proteins. Referring to the latest reports, applications targeting macrophage autophagy have been discussed in CVDs, such as atherosclerosis, myocardial infarction, heart failure, and myocarditis. This review describes a novel approach for future CVD therapies.

FIGURE 1

The role of macrophages in cardiovascular diseases. Low‐density lipoprotein (LDL) penetrates the endothelium and is oxidized into oxidized‐LDL (ox‐LDL), releasing pro‐inflammatory lipids. Activated endothelial cells (ECs) express adhesion molecules to govern circulating monocyte recruitment into the intima. Migrated monocytes differentiate into macrophages, which engulf ox‐LDL and shift into foam cells to enhance lipid core formation. Macrophages can exert different phenotypes and produce various cytokines, which lead to dysfunction of ECs and vascular smooth muscle cells (VSMCs) as well as dysregulation of inflammation, contributing to the development of cardiovascular diseases (CVDs). In the overall process, autophagy plays a great importance role in CVDs via regulating macrophage functions. IL, interleukin; TGF‐β, transforming growth factor‐β.

FIGURE 2

The progress of macroautophagy and mitophagy. Macroautophagy is mediated by autophagosome, the formation of which is initiated by the ULK1 complex, including ULK1, ATG101, FIP200, and ATG13. Following stimulation by amino acids and growth factors, mechanistic target of rapamycin (mTOR) is activated to hinder protein kinase complex by the phosphorylation of ATG13. But, this pathway is inhibited in a state of stress condition and low energy by activation of AMPK. The initiation complex is translocated to a particular domain of the endoplasmic reticulum. To nucleate the autophagosome membrane, ULK1 phosphorylates components of the PI3K complex, composed of Beclin1, ATG14, VPS34, P115, and AMBRA1, and generates phosphatidylinositol 3‐phosphate (PI3P) on autophagosomal precursor membrane. PI3P‐interacting WIPI family proteins (WIPIs) and ATG9‐containing vesicles are also involved. WIPIs recruit the ATG12–ATG5‐ATG16L complex and ATG8s‐PE conjugate into phagophores, essential for membrane elongation and autophagosome closure. ATG8 family proteins on the inner autophagosomal membrane are considered significant for cargo recognition directly by light chain 3 (LC3)‐interacting regions or indirectly by adaptor proteins such as p62/SQSTM1, NBR1, and TAX1BP1. After lysosome fusion, substrate proteins and the inner autophagosomal membrane are degraded to maintain intercellular homeostasis and renovation. PINK1 cannot be cleaved and forms dimers on the outer mitochondrial membrane due to the damaged mitochondrial membrane potential. This leads to Parkin recruitment and conformational changes by phosphorylating the ubiquitin‐like domain at S65. Parkin polyubiquitinates substrates as E3 ubiquitin ligases, which are recognized by autophagy adaptors to activate mitophagy, while TBK1 promotes their interaction with ubiquitin chains. In addition to cardiolipin and autophagy receptors, mitochondrial E3 ubiquitin‐protein ligase 1 (MUL1) not only plays an ubiquitination role, which has multiple common mitochondrial substrates with Parkin, but also directly participates in Parkin‐independent mitophagy as a mitochondrial receptor.

FIGURE 3

Autophagy‐mediated regulation in macrophage functions. Stimuli, such as lipopolysaccharide (LPS) and other stress factors, induce the activation of macrophage autophagy, which influences macrophage functions through various pathways, including macrophage polarization, inflammasome activation, cytokine secretion, metabolism, and phagocytosis. Changed macrophage functions subsequently affect the process and prognosis of cardiovascular diseases. HDL, high‐density lipoprotein; IL, interleukin; ox‐LDL, oxidized low‐density lipoprotein; PPAR, peroxisome proliferator‐activated receptor; SR‐BI, scavenger receptor Class B type I; TLR4, toll‐like receptor‐4.

FIGURE 4

Autophagy in macrophage polarization. miRNA‐mediated epigenetic regulation controls autophagic activity through RNA‐targeted binding to molecules upstream of autophagy, leading to the alternation of macrophage polarization. Furthermore, the activation of the SIRT1‐FOXO1 signalling pathway and application of non‐lethal sonodynamic therapy (NL‐SDT) improve autophagy defect and subsequently favour a shift in M1/M2 equilibrium toward M2. Modification in macrophage polarization can impact the local inflammatory microenvironment, thereby regulating the pathophysiology and development of cardiovascular diseases. Arg1, arginase 1; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP, monocyte chemoattractant protein; mTOR, mechanistic target of rapamycin; TGF‐β, transforming growth factor‐β; TNF‐α, tumour necrosis factor‐α.

FIGURE 5

Autophagy in NLRP3 inflammasome activation. The formation of NLRP3 inflammasome requires two steps: priming and triggering. nuclear factor‐kappaB (NF‐κB) pathway is activated to increase the transcription and translation of NLRP3 inflammasome components and related cytokines as the priming signal. This process is initiated by damage‐associated molecular patterns (DAMPs), which stimulate pathogen‐associated molecular patterns (PAMPs), toll‐like receptors (TLRs), and downstream factors. The damaged mitochondria trigger NLRP3 inflammasome activation. Increased autophagic flux can abrogate the impaired depolarized mitochondrial and mitochondrial reactive oxygen species (mtROS) production through mitophagy. In addition, autophagosome directly engulfs ACS to attenuate its polymerization, thus limiting the activation of NLRP3 inflammasome and associated inflammation. Notably, chaperone‐mediated autophagy is also involved in regulating inflammasome via the degradation of NLRP3 protein. NLRP3 inflammasome can modulate autophagy in turn. The interaction between NLRP3 inflammasome and autophagy is associated with active caspase‐1, which cleaves toll/IL‐1R domain‐containing adaptor‐inducing IFN‐beta (TRIF) to inhibit TLR4‐TRIF‐mediated activation of autophagy. IL, interleukin.

FIGURE 6

Autophagy in metabolism. In terms of lipid metabolism, mechanistic target of rapamycin (mTOR) facilitates glycolysis to upregulate lipid syntheses and pro‐inflammatory gene transcription, such as interleukin (IL)‐1β and IL‐6. And, the progression of AS is exacerbated under mTOR‐mediated suppression of lipophagy and fatty acid oxidation (FAO). While AMP‐activated protein kinase (AMPK) and other autophagy agonists can impact macrophage metabolism via disparate manners, such as cholesterol uptake, lipophagy, and fatty acid synthesis (FAS). FC, free cholesterol; ox‐LDL, oxidized low‐density lipoprotein; TLR, toll‐like receptor.

FIGURE 7

Autophagy in phagocytosis. Macrophages employ receptors that recognize ‘eat me’ signals to uptake dead cells. The engulfment of cellular corpses triggers the recruitment of the PI3K complex to form LAPosome. The interaction of Rubicon (RUBCN) and NOX2 provokes the generation of reactive oxygen species (ROS) required to recruit ATG12–ATG5‐ATG16L and ATG8s‐PE conjugation systems. To initiate light chain 3 (LC3)‐associated phagocytosis (LAP), the decoration of LAPosome is essential for the fusion of the lysosomal network. The photo‐theranostic agent DS‐Ce6 enhances autophagy and recognition receptor Mer tyrosine kinase (MerTK) expression within macrophages, improving lesion efferocytosis. Concurrently, phagocytes will activate retinoid X receptors (RXR), LXR, and peroxisome proliferator‐activated receptor (PPAR) pathways and downstream molecules to initiate the ‘tolerate‐me’ signalling and immunotolerant process. Arg1, arginase 1; IL, interleukin; MerTK, Mer tyrosine kinase; TGF‐β, transforming growth factor‐β.