Lactic acid in macrophage polarization: The significant role in inflammation and cancer

Figures & data

Table 1. Features in different phenotypes of activated macrophages.

	M1 macrophage	M2 macrophage
Stimulate sigals	IFN-γ, TNF-a, LPS, GM-CSF	IL-4, IL-13, IL-10, M-CSF
Metabolic process	Glycolysis, PPP	Oxidative phosphorylation, FAO
Key regulatory enzymes	PFKFB3, mTORC1	PFKFB1, AMPK
Transcription factors	HIF-1a, NF-κB, STAT1, JNK	STAT3, STAT6, PPAR-γ, PGC-1β
Expression markers	CD80, CD86, CD68, MHCII, TLR2, TLR4, iNOS, SOCS3, ROS	CD206, CD163, Arg-1, FIZZ1, YM1/2
Cytokines	TNF-a, IL-1β, IL-6, IL-12, IL-23	IL-10, TGF-β, VEGF
Chemokines	CXCL9, CXCL10, CXCL11, CXCL16	CCL1, CCL13, CCL17, CCL18
Function	Pro-inflammatory; bactericial	Anti-inflammatory; tissue repair; antiparasitic

IFN-γ: interferon-γ; TNF-a: tumor necrosis factor-a; LPS:lipopolysaccharide; GM-CSF: granulocyte-macrophage colony-stimulating factor; IL: interleukin; M-CSF: macrophage colony-stimulating factor; FAO: fatty acid oxidation; PPP: pentose phosphate pathway; mTORC: mammalian target of rapamycin; PFKFB: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; AMPK: Adenosine 5’-monophosphate (AMP)-activated protein kinase; HIF: hypoxia inducible factor; NF-κB: nuclear factor kappa-B; STAT: signal transducer and activator of transcription; JNK: c-Jun N-terminal kinase; PPAR-γ: peroxisome proliferators-activated receptors-γ; PGC-1β: Peroxisome Proliferator-activated Receptor γ Coactivator 1β; MHC: major histocompatibility complex; TLR: Toll-like receptor; iNOS: Inducible Nitric Oxide Synthase; SOCS3: suppressors-of-cytokine-signaling 3; ROS: Reactive oxygen species; Arg-1: Arginase-1; TGF-β: transforming growth factor-β; VEGF: vascular endothelial growth factor;.

Figure 1. The signaling transduction function of lactic acid in macrophage in inflammation. Lactic acid has two main ways to transmit signals to cells: mediated by transporters(McT) or sodium-dependent co-transports (SLC5A8,SlC5A12); And receptors(GPR). i. Lactic acid negative feedback inhibits glycolysis; ii. Lactic acid activates Wnt/?-catenin and Yap/Taz signaling pathway, inhibits NF/?B signaling pathway through GPR on the cell membrane; iii. Lactic acid binds to MAVS and inhibits the interaction of RIG-1; iv. Lactic acid enters the nucleus, binds to histone lysine residues, and directly activates the expression of M2 gene through histone lactylation.

Figure 2. The signaling transduction function of lactic acid in macrophage in cancer. i. Lactic acid activates cAMP and CREM through GPR on the cell membrane. ii. Lactic acid activates mTORC1/ATP6V0D2 pathway and expression of HIF2a; iii. lactic acid activates the expression of transcription factor Nrf2; iv. Lactic acid activates PI3K/ Akt pathway; v. Lactic acid activates the ERK/STAT3 pathway; vi. lactic acid enters the nucleus, binds to histone lysine residues, and directly activates the expression of M2-like genes.