The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review

Table 1 The inducers of macrophage polarization in pathogenesis of PF

Macrophage phenotype	inducer	Mechanism of action	Pathway	References
AM	IL-13	Recruit T cell to lung Levels of IL-4/IL-13↓	Type-2 immunity	[19]
	ECM	M1 activation↑ Expression of IL-6/TNF-α/IL-1β↑	NFκB	[20]
	NLRP3	Accumulated IL-1β/IL-18 induce TGF-β↑	NLRP3	[21, 22]
	oxidized phospholipids	Increasing abnormal lipid surfactant promoted M2 polarization↑	Lipids metabolism	[24]
	ApoE	Expression of Collagen I↑	LPR1	[26]
IM	TLR4/TLR9	Increased IL-6/IL-10/IL-1 receptor antagonist↑	Toll-like receptor	[29]
IM	CSF1R	Higher level of Arg-1 than AMs↑	CSF1/CSF1R	[30]
M1	LPS	Secretion of pro-inflammatory IL-6/ TNF-α↑	LPS/TLR4	[34]
	MEF2C	Expression of IL-12a/IL-2b↑	IL-12	[35]
	LPS/IL-4	Gene levels of IL-6/IL-9/IL-15↑	IL12/Arg	[36]
	IFN-γ	Gene levels of JAK1/JAK2/TYK2↑	JAK/STAT	[37]
	LPS/IFN-γ	Levels of CXCL10, IL-6 and TNFα↑	JAKs	[38]
	ROS	Upregulation TGF-β1, Smad2, Smad3, COL1A1, α-SMA, and MMP2↑ Downregulation of Smad7 and TIMP2↓	TGF-β/Smad2/3	[42]
M2	TGF-β1 and p-Smad2/3	Upregulation of TGF-β1 and p-Smad2/3 promotes EMT↑	TGF-β1/Smad2/3	[45, 46]
	STAT6	Upregulation of IL-4, IL-13 and STAT6↑	IL4/IL-13	[47]
	IL-4, 5, and 13	IL-4, 5, and 13 protein synthesis decrease Arg-1↓	NKT/Th2	[48]
	MMP-10	Promoted M2 phenotypes with increased collagenase activity↑	Collagen degradation	[49]
	MMP-28	Enhanced IL-6↑ Downregulation of Arg-1 and Ym1↓	EMT	[50]

↑ Increase, ↓ Decrease, IL Interleukin, ECM Extracellular matrix, TGF-β1 Transforming growth factor-beta, TNF-α Tumor Necrosis Factor-α, NF-κB Nuclear factor kappa-light-chain-enhancer of activated B-cells, NLRP3 NLR Family Pyrin Domain Containing 3, ApoE Apolipoprotein E, LPR1 Lipoprotein receptor-related protein 1, TLR Toll-like receptors, CSF1R Clinically available colony-stimulating factor receptor-1, LPS Lipopolysaccharides, IFN-γ Interferon-γ, MEF2C Myocyte enhancer factor 2 C, STAT6 Signal Transducer And Activator Of Transcription 6, MMP Matrix metallopro

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