The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization

Abstract

Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization.

Keywords: Hippo; inflammatory diseases; macrophage polarization; metabolism; regulatory network.

Figure 1

Characteristics of polarized macrophages. M0 macrophages polarize into M1 macrophages with IFN-γ, TNF, DAMPs (e.g., ATP), and PAMPs (e.g., LPS) stimuli. M1 macrophages secrete pro-inflammatory cytokines (e.g., TNF, IL-1β, IL-6) and free radicals (NO, ROS) to perform pro-inflammatory, bactericidal, viricidal, and antineoplastic activities. In M1 macrophages, glycolysis, PPP, and de novo FAS are upregulated, and OXPHOS and the intact TCA cycle are downregulated. M0 macrophages polarize into M2 macrophages with IL-4, IL-10, IL-13, and TGF-β treatment. M2 macrophages secrete anti-inflammatory cytokines (e.g., IL-10, IL-1RII, IL-1RA) and growth factors (e.g., TGF-β1, PDGF) to perform anti-inflammatory, matrix-producing, pro-angiogenesis, and pro-wound healing functions. In M2 macrophages, FAO, OXPHOS, and the TCA cycle are upregulated. In special cases, M1 can be polarized toward M2. However, whether M2 can be polarized to M1 is still debated. M0 macrophages, unactivated macrophages; M1 macrophages, classically activated macrophages; M2 macrophages, alternatively activated macrophages; IFN, interferon; TNF, tumor necrosis factor; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; PPP, pentose phosphate pathway; OXPHOS, oxidative phosphorylation; FAS, fatty acid synthesis; FAO, fatty acid oxidation; TCA, tricarboxylic acid cycle; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TGF, transforming growth factor; PDGF, platelet-derived growth factor.

Figure 2

Macrophage polarization in different diseases. (A) Macrophages recognize lipopeptides, LPS, flagellin, and the low-methylated DNA sugar backbone of bacteria through TLR2/4/5/9 and recognize CpG dsRNA, ssRNA, and unmethylated DNA of viruses through TLR3/7/9 to activate M1 macrophages. Activated M1 macrophages secrete proinflammatory cytokines and upregulate MHC-II, CD86, CD80, and CD40. Macrophages recognize lipoprotein, CpG DNA, and ssRNA and profilin of parasites through TLR2/7/9/11 to polarize into M2 macrophages. M2 macrophages produce Arg-1, TGF-β, VEGF, YM1, and IGF-1. (B) In RA, SLE, glomerulonephritis, obesity, diabetes, and atherosclerosis, macrophages are overactivated to upregulate the transcription of proinflammatory cytokines such as IL-1β, TNF, and CCL2 and downregulate the transcription of anti-inflammatory cytokines such as IL-10, Ym-1, and Arg-1. In fibrosis and tumors, M2 macrophages are overactivated to upregulate anti-inflammatory cytokines such as IL-10, TGF-β, and Wnt-1. TLR, toll-like receptor; MHC, major histocompatibility complex; CD, cluster of differentiation; VEGF, vascular endothelial growth factor; IGF, insulin-like growth factor; CCL, chemokine cc-motif ligand; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Figure 3

The metabolism of regulated polarization. (A) Under LPS, IFN-γ, or TNF treatment, glycolysis, PPP, and FAS are upregulated to increase M1 polarization. The TCA cycle and amino acid metabolism are changed. The changes promote intermediate products of TCA and NO production of large quantities to enhance pro-inflammation and kill bacteria. Glucose uptake is increased and further produces pyruvate. Pyruvate enters mitochondria and promotes citrate, itaconate, and succinate accumulation. Citrate enters the cytoplasm to produce acetyl-CoA, which participates in histone acetylation and FAS. Succinate enters the cytoplasm to maintain the stabilization of HIF-1α. HIF-1α translocates into the nucleus to transcribe glycolysis enzymes and proinflammatory cytokines. In addition, IDO is downregulated to inhibit kynurenine production to increase M1 polarization. Ribulose-5-phosphate and CARKL are decreased to inhibit M1 polarization. Glutamine plays a negative role in pro-inflammatory cytokine production. (B) Response to IL-4, TCA cycle, FAO, and OXPHOS is upregulated for M2 polarization. Amino acid metabolism is changed to enhance anti-inflammatory cytokine production. The intermediate products of TCA and FAO are involved in OXPHOS. In response to IL-4 and lactate, M2 markers such as Arg-1 are transcribed. Arg-1 promotes arginine catabolism and further enhances TCA and OXPHOS. In addition, IDO is upregulated to increase kynurenine production. Ribulose-5-phosphate and CARKL are increased. These changes enhance M2 polarization. Glutamine plays a positive role in M2 polarization. PK, pyruvate kinase; PGD, phosphogluconate dehydrogenase; PDH, pyruvate dehydrogenase complex hyperacetylation; CS, citrate synthase; ACOD, aconitase decarboxylase; SDH, succinate dehydrogenase; IDH, isocitrate dehydrogenase; iNOS, inducible nitric oxide synthase; IDO, indoleamine 2,3-dioxygenase; HIF, hypoxia-inducible factor; NAD, nicotinamide adenine dinucleotide; ATP, adenosine 5’-triphosphate.

Figure 4

Pathways of regulatoy metabolism. (A) In M1 polarization, PI3K-AKT-mTOR, MEK/ERK, and NF-κB are activated to enhance glycolysis through HIF-1α. In addition, PI3K-AKT-mTOR and NF-κB also directly regulate glycolysis. JAK/STAT increases arginine metabolism by iNOS. NO that is produced by the enzymolysis of iNOS participates in the TCA cycle. JAK/STAT and NF-κB regulate the TCA cycle through IRG1. Notch affects the TCA cycle via PDP1. CD40-AMPK enhances FAO by regulating the conversion of glutamine and lactate. (B) In M2 polarization, PPARγ enhances FAO by increasing CD36 expression. AMPK/PPARα promotes FAO. PI3K-AKT-mTORC2 increases the level of FAO via IRF4. STAT6 boosts FAO, FAS, and arginine metabolism via IRF4, SREBP1, and Arg-1, respectively. AMPK-mTORC1 increases FAS by ACLY. PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-B; MEK, mitogen-activated extracellular signal-regulated kinase; ERK, extracellular regulated protein kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; AMPK, adenosine 5’-monophosphate (AMP)-activated protein kinase; PPAR, peroxisome proliferator-activated receptor.

Figure 5

Crosstalk with Hippo and other pathways. Hippo engages in crosstalk with NF-κB, HIF-1α, MEK/ERK, and PI3K-AKT-mTOR to affect glycolysis. Hippo engages in crosstalk with PI3K-AKT-mTOR, PPARγ, and AMPK to affect FAO. Hippo engages in crosstalk with Notch to affect arginine metabolism. Hippo engages in crosstalk with Notch and NF-κB to affect the TCA cycle.