Table 2.

Integrin expression and function in wound cells

Integrin	Wound Cells Expressing	Ligands in Wounds	Cellular Functions in Wound Healing	Wound Phenotypes in Animal Models
α1β1	ECs, FBLs, monocytes, macrophages, and myofibroblasts	COL I, III, IV, and V, LM-111	Mediates VEGF-driven angiogenesis, negative feedback regulation of collagen synthesis in FBLs	The integrin α1 null mice exhibit increased collagen gene expression during early granulation tissue development and altered collagen fibril distribution
α2β1	Platelets, KCs, ECs, and FBLs	COLs (types I and III with high affinity), LM-332, TN-C, MMP-1, and CCN1/Cyr6	Mediates KC migration and VEGF-driven angiogenesis, may mediate platelet adhesion to COL, and contribute to collagen polymerization by FBLs	Increased wound angiogenesis in α2 integrin knockout mice
α3β1	KCs, ECs, and FBLs	LM-332, other LMs	Regulates KC polarization during re-epithelialization, controls angiogenesis and TGF-β1–mediated responses	Integrin α3 null mice die shortly after birth with skin blisters and disrupted basement membranes; KC-targeted α3 integrin knockout mice exhibit slightly accelerated or not affected wound closure but impaired wound angiogenesis; retarded re-epithelialization α3 integrin null mouse skin grafts
α4β1	Leukocytes, FBLs, and ECs	EDA-FN, OPN, several ADAMs, VCAM-1, and EMILIN1	Interaction with EMILIN1 may control FBL proliferation and TGF-β1 processing	Genetic ablation of α4 integrin causes an embryonic lethal phenotype
α5β1	Platelets, KCs, ECs, FBLs, and leukocytes	FN, CCN2/CTGF, and CCN3/NOV	Promotes KC migration, may be involved in platelet–blood vessel wall interactions	Genetic ablation of α5 integrin causes an embryonic lethal phenotype
α6β1	Platelets, ECs, leukocytes, and FBLs	LMs, TSPs, CCN1/Cyr6, CCN2/CTGF, and CCN3/NOV	May be involved in platelet–blood vessel wall interactions and angiogenesis; interaction with CCN1/Cyr61 promotes myofibroblast senescence and controls fibrogenesis	Genetic ablation of α6 integrin causes a neonatal lethal phenotype; endothelial cell-targeted deletion of α6 integrin increases tumor angiogenesis but reduces postischemic vascular repair—these phenotypes may be partly caused by the loss of α6β4 in these cells as well; no wound healing data available
α7β1	N/A (expressed by muscle cells, vascular smooth muscle cells, and in neurons)	TN-C, LM
α8β1	Myofibroblasts	FN, VN, TN-C, and latent TGF-β1	May contribute to fibrotic responses	No wound healing data available
α9β1	KCs, FBLs, neutrophils, and ECs	EDA-FN, TN-C, OPN, several ADAMs, EMILIN1, and VEGFs	Regulates KC and FBL growth, neutrophil chemotaxis as well as EC migration and angiogenesis	Reduced keratinocyte proliferation and delayed wound closure in keratinocyte-targeted α9 integrin knockout mice; impaired formation of granulation tissue in mouse wounds treated with a blocking antibody against α9 integrin because of reduced adhesion and migration of FBLs
α10β1	FBLs?	COLs	May mediate FBL adhesion to collagen	No wound healing data available
α11β1	FBLs	COLs	Controls myofibroblast differentiation and may mediate FBL adhesion to collagen and contribute to collagen reorganization	No wound healing data available
αvβ1	KCs, ECs	FN, VN, OPN, and latent TGF-β1	Mediates KC adhesion during re-epithelialization	Difficult to address the specific function of this receptor due to the wide array of αv and β1 integrins
αvβ3	ECs, platelets, FBLs, and macrophages	Fibrin(ogen),TN-C, OPN, latent TGF-β1, CCN1/Cyr6, CCN2/CTGF, and CCN3/NOV	Required for neoangiogenesis, modulates fibrin network structure and stability, mediates EC adhesion to CCN1/Cyr6 and CCN2/CTGF, EC survival, pericyte retention in blood vessels, and FBL proliferation	Mice lacking β3 integrin subunit show enhanced re-epithelialization but reduced KC proliferation due to increased TGF-β1 and enhanced dermal fibroblast infiltration into the wound. They also exhibit reduced macrophage numbers in wounds and increased angiogenesis in late wound healing. Peptide antagonists of αvβ3 integrin reduce granulation tissue formation and wound-induced angiogenesis in porcine wounds
αvβ5	ECs, FBLs, and skin KCs	VN, OPN, latent TGF-β1, CCN1/Cyr6, CCN3/NOV, VEGF	May participate in FBL transformation to myofibroblasts, interaction with CCN1/Cyr61 mediates FBL migration	Wound healing is normal in β5 integrin knockout mice
αvβ6	KCs	FN, VN, TN-C, latent TGF-β1 and -β3, and chromogranin A	Regulates inflammation and KC proliferation, contributes to basement membrane and granulation tissue remodeling	Re-epithelialization is normal in β6 integrin knockout mice if not challenged by age or diabetes; mice with keratinocyte-targeted β6 integrin overexpression are susceptible to chronic, nonhealing wounds but show faster re-epithelialization than wild-type mice after being challenged by a glucocorticoid treatment
αvβ8	Dentritic cells, FBLs, and ECs	LM-111, COL IV, FN, and latent TGF-β1	May regulate inflammation through TGF-β activation	No wound healing data available
α6β4	KCs, ECs	LM-332, other LMs	Promotes KC adhesion, migration and proliferation, and EGFR signaling; regulates angiogenesis in ECs	Genetic ablation of β4 integrin causes a neonatal lethal phenotype with severe epidermal blistering; deletion of β4 integrin intracellular signaling domain caused decelerated wound re-epithelialization and reduced keratinocyte migration
αIIbβ3	Platelets	Fibrin(ogen), FN, COL, VWF, CCN1/Cyr6, and CCN2/CTGF	Mediates platelet aggregation in clot formation, modulates fibrin network structure and stability	An antagonist of αIIbβ3 integrin has an antithrombotic effect in mice
α4β7	Leukocytes, dentritic cells	OPN, VCAM,	Involved in leukocyte extravasation	Impaired immune response in β7 integrin knockout mice due to defective T-cell trafficking, no wound healing data available
αEβ7	T-lymphocytes, dentritic cells	E-cadherin	Mediates leukocyte extravasation	Inflammatory skin lesions in αE integrin knockout mice, no wound healing data available
αLβ2 (LFA-1)	All leucocytes	Several ICAMs, JAM-1, and lumican	Mediates leukocyte extravasation across the endothelium	No wound healing data available
αMβ2 (Mac-1)	Monocytes, macrophages, NK, neutrophils, and T-cells	Fibrin(ogen), several ICAMs, heparin, plasminogen, FN, LMs, COL I, uPAR, CCN1/Cyr6, CCN2/CTGF, and others	Involved in leukocyte extravasation across the endothelium; promotes fibrinolysis and clearance of fibrin clots by monocytes and neutrophils in complex with uPAR and its ligand uPA	Attenuation of granulation tissue deposition and wound re-epithelialization in αM integrin knockout mice
αXβ2	Monocytes, macrophages, dentritic cells, and NK	Fibrin(ogen), several ICAMs, COL I, heparin, and OPN	Involved in leukocyte extravasation	No wound healing data available
αDβ2	Macrophages, eosinophils	ICAM-3, VCAM-1, and CCN1/Cyr6	Involved in leukocyte extravasation	No wound healing data available

The data is consolidated from the following articles: Häkkinen et al.,⁸ Koivisto et al.,¹¹ Senger and Davis,¹² Gardner et al.,⁴⁷ Bouvard et al.,⁴⁸ Grüner et al.,⁴⁹ Reynolds et al.,⁵⁰ AlDahlawi et al.,⁵¹ Grenache et al.,⁵² Sisco et al.,⁵³ Blue et al.,⁵⁴ Mitchell et al.,⁵⁵ Nieswandt et al.,⁵⁶ Germain et al.,⁵⁷ Jacobsen et al.,⁵⁸ Nakayama et al.,⁵⁹ Chen and Lau,⁶⁰ Oommen et al.,⁶¹ Worthington et al.,⁶² Bouvard et al.,⁶³ Høye et al.,⁶⁴ and Tan.⁶⁵

ADAM, a disintegrin and metalloproteinase; CCN, Cyr61-CTGF-Nov; COL, collagen; CT, connective tissue; EDA, extra domain A; EC, endothelial cell; EGFR, epidermal growth factor receptor; FBL, fibroblast; FN, fibronectin; ICAM, intercellular adhesion molecule; KC, keratinocyte; LM, laminin; NK, natural killer cell; OPN, osteopontin; TGF, transforming growth factor; TN, tenascin; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; VN, vitronectin; VWF, von Willebrand factor.