What Is the Impact of Depletion of Immunoregulatory Genes on Wound Healing? A Systematic Review of Preclinical Evidence

Table 1

Main results of the gene depletion on immunoregulatory molecules involved with wound healing of knockout mice compared to the wild type.

References	Gene depletion	Predicted location	WH	Proinflammatory function	Anti-inflammatory function	Both function	Healing mechanisms
Ortega et al. (1998) [35]	bFGF	EC/I	D	Ø bFGF			(D) crust thickness, reepithelization
Lin et al. (2003) [26]	IL-6	EC/I	D	↓IL-1α, IL-1β, VEGF		↓TGF-β1	↓Neutrophil, macrophage, collagen production, angiogenesis; = fibrinogen, platelet
Ishida et al. (2004) [41]	IFN-γ	EC	A	= IL-12, IL-18; ↑VEGF		↑TGF-β1	↓Macrophages; ↑angiogenesis, collagen deposition
Guo et al. (1996) [38]	KGF	EC/ I	U	Ø KGF, = aFGF, bFGF, EGF, TNF-α			(U) reepithelization
Fang et al. (2007) [51]	GM-CSF	EC	D			of constitutive expression	↑(D) collagen deposition; ↓acute inflammatory response; = microvessel number
Yamauchi et al. (2016) [44]	α-kl	EC/M	D	↑IL-1β, TNF-α		↑IL-6	↓Collagen fibers, formation of the granulation tissue
Thuraisingam et al. (2006) [50]	Nramp1	M	D			↑TGF-β	—
Cogliati et al. (2015) [48]	Cx43	M	A			↑TGF-β1	= Collagen deposition; ↑proliferation and activation of dermal fibroblasts
Braun et al. (2002) [56]	Nrf2	I	U	↓IL-1β, TNF-α		↓IL-6	(D) EC molecules
Thuraisingam et al. (2010) [49]	MK2	I	D	↓GM-CSF, VEGF, TNF, IL-1β		↓IL-6, IFN-γ	↓Angiogenesis, collagen deposition; = neutrophils and macrophages
Somanath et al. (2008) [40]	Akt1	I	U	↓VEGF			↓Vascularization, collagen fibers, macrophages
Ashcroft et al. (1999) [39]	Smad3	I	A			↓TGF-β1	(A) reepithelization, ↓fibroblasts, and inflammatory cells
Kopecki et al. (2007) [57]	c-Myb	I	D			↑TGF-β1	↓Collagen deposition, cell proliferation
Wang et al. (2017) [28]	P311	I	D	↓VEGF		↓TGF-β1	↓Neoangiogenesis, tissue granulation remodeling, neocapillaries, reepithelization, length of the neoepithelium
Cheng et al. (2017) [27]	P311	I	U	↓TGF-β2	↓TGF-β3	↓TGF-β1	↓Collagen deposition, stiffness, and tensile strength in scars
Agah et al. (2002) [36]	TSP1 and TSP2	EC	TSP1 = D; TSP2 = A			TSP1 = ↓TGF-β1; TSP2 = TGF-β1	TPS1 = ↓collagen fibers, macrophages; = vascularization; TPS2 = ↓organization collagen fibers, matrix metalloproteinase expression; ↑neovascularization
MacLauchlan et al. (2009) [37]	TSP2	EC	A	↑VEGF			= Collagen fibers, tensile strength, proliferation, myofibroblast differentiation
Gutiérrez-Fernández et al. (2007) [54]	MMP8	EC/I	D			↓TGF-β1	(D) reepithelization
Hattori et al. (2009) [42]	MMP9 and MMP13	EC	MMP9 = D; MMP13 = D	MMP9 = ↓intact CTGF; MMP13 = ↑intact CTGF			(D) reepithelization; = infiltration of inflammatory cells
Yeh et al. (2010) [55]	Lum	EC	D			↑TGF-β1 just was at day 6	↑Macrophages, inflammatory cells; ↓skin thickness
Zhang et al. (2012) [52]	Mstn	EC	D			↓TGF-β	(D) reepithelization and wound contraction; ↓collagen deposition, fibroblast-to-myofibroblast transformation
Zigrino et al. (2012) [47]	MMP14	I/M	D	= VEGF			= Formation of the granulation tissue, epidermal differentiation, formation; ↑vascularization
Maeda et al. (2011) [43]	ICOS and ICOSL	ICOS = M; ICOSL = I/M	ICOS = D; ICOSL = D	↓TNF-α, CTGF; = PDGF, VEGF	↓IL-4, IL-10	↓IL-6; = TGF-β, IFN-γ	↓Granulation tissue formation, vascularization, myofibroblasts proliferation, neutrophils, and macrophages infiltration
Kümin et al. (2007) [45]	Prdx6	I	U	= VEGF, IL-1β		= TGF-β1	= Area of hyperproliferative
Lundvig et al. (2014) [53]	HO-2	EC/I/M	D	= TNF	= Ang-1	= Ang-2	↓Collagen deposition
Guimarães et al. (2018) [29]	5-LO	I	A	↓TNF-α	= IL-10	↓TGF-β	↓Inflammatory infiltrate, mast cells, lymphocytes, matrix metalloproteinase expression; ↑collagen deposition
Eming et al. (2007) [46]	IL-10	EC/I	A	↑VEGF-A-expressing mononuclear cells			(A) reepithelization; ↑angiogenesis, myofibroblast differentiation, macrophages infiltration, collagen deposition; ↓breakdown force

EC: extracellular; M: membrane; I: intracellular; WH: wound healing; ↑: increase; ↓: reduction; =: similar; Ø: absence: (D): delayed; (A): accelerated; (U): unchanged. 5-LO: 5-Lipoxygenase; aFGF: acid Fibroblastic Growth Factor; α-kl: alpha-Klotho; (Ang-1, Ang-2): Angiopoietin; bFGF: basic Fibroblastic Growth Factor; CTGF: Connective Tissue Growth Factor; Cx43: Connexin 43; EGF: Epidermal Growth Factor; GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor; HO-2: Heme Oxygenase 2; ICOS: Inducible Costimulator; ICOSL: Inducible Costimulator Ligand; IFN-γ: Interferon-gama; (IL-10, IL-6, IL-4, IL-12, IL-18, IL-1β, IL-1α): interleukins; KGF: Keratinocyte Growth Factor; Lum: Lumican; (MMP8, MMP9, MMP13, MMP14): Matrix Metalloproteinase; MK2: Mitogen-Activated Protein Kinase-2; Mstn: Myostatin; Nramp: Natural resistance-associated macrophage proteins; P311: Neuronal protein 3.1; Prdx6: Peroxiredoxin 6; PDGF: Platelet-Derived Growth Factor; Akt1: Serine/threonine kinase; (TPS1, TPS2): Thrombospondin; Nrf2: Transcription factor NF-E2-related factor 2; c-Myb: Transcription factor proto-oncogene c-Myb; (TGF-β, TGF-β1, TGF-β2, TGF-β3): Transforming Growth Factor; (TNF, TNF-α): Tumor Necrosis Factor; (VEGF, VEGF-A): Vascular Endothelial Growth Factor.