Integrins in Health and Disease: Key Effectors of Cell-Matrix and Cell-Cell Interactions

Preface
Contents
About the Editors
Part I: Knockouts and Animal Models
	Integrins α1β1 and α2β1: The Generalist Collagen Receptors
		1 Integrins α1β1 and α2β1: Abundant Expression
		2 Ligands: Not Only Collagen Receptors
		3 Functions: Development
		4 Functions: Cell Proliferation
		5 Functions: Platelets
		6 Functions: ECM Remodelling
		7 Functions: Angiogenesis
		8 Functions: Retina
		9 Functions: Immunity
		10 In Vivo Functions Unveiled by Integrin Inhibitors
		11 Signalling by α1β1 and α2β1
		12 Conclusions
		References
	Roles for Integrin α3β1 in Development and Disease
		1 Introduction
		2 Integrin α3β1: A Historical Perspective
			2.1 The Integrin Family of Cell Adhesion Receptors
			2.2 Integrin α3β1
		3 Basic Cell Adhesion and Signaling Functions of Integrin α3β1
			3.1 Regulation of Cell Adhesion and Migration by α3β1
			3.2 Regulation of Signal Transduction by α3β1
				3.2.1 FAK-Src Signaling Pathways
				3.2.2 Akt and STAT3 Signaling Pathways
				3.2.3 Hippo and YAP/TAZ Signaling Pathways
				3.2.4 TGF-β Signaling Pathways
			3.3 Regulation of Basement Membrane Assembly and Integrity by α3β1
			3.4 Modulation of Gene Expression Programs by α3β1
				3.4.1 Regulation of Post-Transcriptional mRNA Stability
				3.4.2 Regulation of Gene Transcription
			3.5 Modes of Regulating α3β1 Function
				3.5.1 Glycosylation
				3.5.2 Physical Interactions with Integrin-Associated Proteins
				3.5.3 Functional Interactions with Other Integrins
		4 Roles for Integrin α3β1 in Organ Development and Function
			4.1 Kidney
			4.2 Lung
			4.3 Salivary Gland
			4.4 Mammary Gland
			4.5 Vasculature
			4.6 Skin
		5 Roles for Integrin α3β1 in Cutaneous Wound Healing
			5.1 Regulation of Cell-Intrinsic Functions of Wound Keratinocytes
			5.2 Regulation of Basement Membrane Regeneration
			5.3 Regulation of the Keratinocyte Secretome
				5.3.1 Modification of the Stromal Extracellular Matrix
				5.3.2 Paracrine Crosstalk to Stromal Cells
		6 Roles for Integrin α3β1 in Cancer
			6.1 Cancer-Supportive Roles for α3β1 in Tumor Cells
				6.1.1 Pro-tumorigenic Roles
				6.1.2 Pro-invasive/Pro-metastatic Roles
			6.2 Cancer-Suppressive Roles for α3β1 in Tumor Cells
			6.3 Roles for α3β1 in Cancer-Associated Stromal Cells
		7 Prospects for Integrin α3β1 as a Potential Therapeutic Target
			7.1 α3β1 as a Potential Target for Cancer Therapies
			7.2 α3β1 as a Potential Target for Wound Therapies
		8 Conclusions and Future Perspectives
		References
Part II: Fibrosis and Cancer
	Integrins: Key Targets in Tissue Fibrosis and Tumor Stroma
		1 Integrins
			1.1 Integrin Signaling
		2 Integrins in Tissue and Tumor Fibrosis
			2.1 Integrins in Pulmonary Fibrosis
				2.1.1 Role of Integrin αv Subunit in Pulmonary Fibrosis
				2.1.2 Role of Integrin Subunits α2 and α11 in Pulmonary Fibrosis
				2.1.3 Role of Integrin Subunit α3 in Pulmonary Fibrosis
				2.1.4 Role of Integrin α5 Subunit in Pulmonary Fibrosis
			2.2 Integrins in Liver Fibrosis
				2.2.1 Role of Integrin Subunit β1 in Liver Fibrosis
				2.2.2 Role of Integrin Subunit αv in Liver Fibrosis
				2.2.3 Role of Integrin Subunit α5 in Liver Fibrosis
				2.2.4 Role of Integrin Subunit α8 in Liver Fibrosis
				2.2.5 Role of Integrin Subunit α11 in Liver Fibrosis
			2.3 Integrins in Cardiac Fibrosis
				2.3.1 Role of Integrin Subunits β1 and β3 in Cardiac Fibrosis
				2.3.2 Role of Integrin Subunit αv in Cardiac Fibrosis
				2.3.3 Role of Integrin Subunits α2 and α11 in Cardiac Fibrosis
				2.3.4 Role of Integrin Subunit α5 in Cardiac Fibrosis
			2.4 Integrins in Renal Fibrosis
				2.4.1 Role of Integrin Subunit β1 in Renal Fibrosis
				2.4.2 Role of Integrin Subunit αv in Renal Fibrosis
				2.4.3 Role of Integrin Subunits α2 and α11 in Renal Fibrosis
				2.4.4 Role of Integrin Subunit α3 in Renal Fibrosis
				2.4.5 Role of Integrin Subunit α8 in Renal Fibrosis
			2.5 Integrins in Tumor Fibrosis
				2.5.1 Role of Integrin Subunit α11 in Tumor Fibrosis
				2.5.2 Role of Integrin Subunits α5 and α3 in Tumor Fibrosis
				2.5.3 Role of Other Integrins in Tumor Fibrosis
			2.6 Conclusion
		References
	Integrins in Cardiac Form, Function, and Disease
		1 Introduction
		2 Myocyte Integrin and Integrin-Complex Protein Function in Large Animal Models and Humans
		3 Integrins, Integrin-related Proteins, and Ion Channels
		4 Integrins and Mechanotransduction in Cardiac Myocytes
		5 Integrins and Related Proteins in Cardiac Fibroblasts and Fibrosis
		6 Integrins as Therapeutics in Cardiac Disease
		7 Conclusions and Future Perspectives
		References
	Integrin α8 and Its Ligand Nephronectin in Health and Disease
		1 Introduction
		2 Integrin α8 Structure and Expression
		3 Major Ligands of Integrin α8
		4 Generation and Initial Characterization of Integrin α8-Deficient Mice
		5 Nephronectin as a Ligand of Integrin α8 in the Kidney
		6 Additional Characteristics of Nephronectin
		7 Integrin α8 and Nephronectin in Tissue Development, Homeostasis, and Disease
		8 Smooth Muscle Cells
			8.1 Vascular Smooth Muscle Cells
			8.2 Visceral Smooth Muscle Cells
		9 Kidney
			9.1 Kidney Homeostasis
			9.2 Animal Models of Kidney Diseases
			9.3 Human Kidney Diseases and Developmental Disorders
		10 Lung
			10.1 Development and Homeostasis in the Lung
			10.2 Injury and Fibrosis in the Lung
			10.3 Airway Obstructive Diseases
		11 Other Organs
			11.1 Liver
			11.2 Heart
			11.3 Skin
			11.4 Brain and Nervous System
		12 Cancer Biology
		13 Conclusions and Future Perspectives
		References
	αv Integrin-Dependent TGFβ Activation in Cancer: A Brief Update
		1 Introduction
		2 Role of the GARP-LTGFB-αvβ8 Axis in Promoting Cancer
		3 Non-Treg Roles of αvβ8 Activation of TGFβ in Cancer
		4 Targeting Integrin-Dependent TGFβ Signalling in Cancer
		5 Conclusion
		References
Part III: Human Disease
	α11β1: A Mesenchymal Collagen-Binding Integrin with a Central Role in Tissue and Tumor Fibrosis
		1 Introduction
		2 Re-definition of Fibroblast Heterogeneity
		3 Integrin α11β1 in Wound Healing
		4 Integrin α11β1 in Tissue Fibrosis
			4.1 Integrin α11 in Skin Fibrosis
			4.2 Integrin α11 in Cardiac Fibrosis
			4.3 Integrin α11 in Fibrotic Lung
			4.4 Integrin α11 in Fibrotic Liver
		5 Integrin α11β1 in Tumor Fibrosis
			5.1 Integrin α11 in Non-Small Cell Lung Carcinoma (NSCLC)
			5.2 Integrin α11 in Breast Cancer
			5.3 Integrin α11 in Pancreatic Cancer
		6 Integrin α11 Tools for Fibrosis Studies and Therapeutics
			6.1 Monoclonal Antibodies Directed Against Human Integrin α11
			6.2 ITGA11-Driver Cre Mouse Strain
		7 Conclusion
		References
	Integrins in Pathological Tissue Remodelling of Joints
		1 Introduction
		2 Integrins in the Pathogenesis of Osteoarthritis
			2.1 Changes in the Expression of Integrins in OA
			2.2 Functional Consequences of Altered Integrin Expression in OA
			2.3 Therapeutic Strategies Targeting Integrins in OA
		3 Integrins in the Pathogenesis of Rheumatoid Arthritis
			3.1 Expression and Function of Integrins in RA-Fibroblast-like Synoviocytes
			3.2 Role of Cartilage Damage in Attachment and Cellular Activation of RA-Fibroblast-like Synoviocytes
			3.3 Integrins in the Regulation of Joint Inflammation and Autoimmunity in RA
			3.4 Therapeutic Approaches Targeting Integrins in RA
		4 Conclusions
		References
	α4 Integrins in Immune Homeostasis and Disease
		1 Introduction
		2 Structure of α4 Integrins
			2.1 Extracellular Domain
			2.2 Transmembrane Domains
			2.3 Cytoplasmic Domains
		3 Extracellular Ligands for α4 Integrins
			3.1 VCAM-1
			3.2 MAdCAM-1
			3.3 FN
			3.4 Gp120
			3.5 Osteopontin
			3.6 Invasin
			3.7 Other α4 Extracellular Domain-Binding Proteins
		4 Intracellular Adaptor Proteins for α4 Integrins
			4.1 β1 and β7 Cytoplasmic Tail-Binding Proteins
				4.1.1 Talin
				4.1.2 Kindlin
				4.1.3 Filamin
			4.2 α4 Cytoplasmic Tail-Binding Proteins
				4.2.1 SHARPIN
				4.2.2 MDGI
				4.2.3 Paxillin
				4.2.4 Hsp90
		5 Activation of α4 Integrins
			5.1 Affinity Regulation
			5.2 Avidity Regulation
		6 Expression and Physiological Functions of α4 Integrins
			6.1 Expression of Integrin α4β1 and α4β7
			6.2 Integrin α4β1 and α4β7 in Leukocyte Homing
			6.3 Integrin α4β7 in Lymphocyte Gut-Tropic Trafficking and GALT Formation
			6.4 Role of Integrin α4β7 in Innate Immune Cells
			6.5 Integrin α4β1 in T-Cell Proliferation, Activation, and Survival
			6.6 Integrin α4β1 in Hematopoietic Stem Cell Maintenance and Hematopoiesis
			6.7 Integrin α4β1 and Embryonic Development
		7 α4 Integrins in Disease
			7.1 α4 Integrins in Cancer
			7.2 Integrin α4β1 in Multiple Sclerosis (MS)
			7.3 Integrin α4β7 in Inflammatory Bowel Disease (IBD)
			7.4 Integrin α4β7 in Acquired Immunodeficiency Syndrome (AIDS)
			7.5 Integrin α4β7 in Graft-Versus-Host Disease
		8 Conclusion and Future Perspectives
		References
	β2-integrins in Immunity: New Roles for Old Players
		1 Introduction
			1.1 β2-integrins
		2 β2-integrin Structure
		3 Structural Changes Associated with β2-integrin Activation
		4 β2-integrin Cytoplasmic Domains and Phosphorylation
		5 β2-integrin Ligands
		6 β2-integrin Regulation by Cytoplasmic Proteins
			6.1 Talin
			6.2 Kindlin-3
			6.3 Filamin A
			6.4 Others
		7 Inside-out Signaling and Integrin Activation
		8 Mechanosignaling by β2-integrins
		9 β2-integrin Roles in Immune Cells
			9.1 Neutrophils; Trafficking and Effector Functions
			9.2 Macrophages; Phagocytosis and Signaling
			9.3 Dendritic Cells; Restriction of Maturation, Migration, and APC Function
			9.4 T cells; Trafficking, Activation and Differentiation
			9.5 B cells: Homing, Immunological Synapse Formation, and Tolerance
		10 Leukocyte Adhesion Deficiency: When β2-integrins Go Wrong
			10.1 LAD-I
			10.2 LAD-III
		11 β2-integrins and Infections: Evidence from Mice and Men
		12 Inflammatory Diseases
			12.1 Systemic Lupus Erythematosus
			12.2 Multiple Sclerosis
			12.3 Obesity and Atherosclerosis
			12.4 Rheumatoid Arthritis
		13 β2-integrins in Cancer
			13.1 β2-integrins Affect Immune Cell Recruitment to Tumors
			13.2 β2-integrins Enhance Effector Function of Cytotoxic Cells in the TME
			13.3 β2-integrins Suppress Dendritic Cell-mediated Anti-tumor Responses
			13.4 β2-integrins Promote Suppressive Immune Cell Populations in the TME
			13.5 β2-integrins Also Have Cell Intrinsic Effects on Cancer Cells
		14 Therapy Targeting β2-integrins
			14.1 Cancer Therapy Targeting β2-integrins
		15 Concluding Remarks and Future Outlook
		References
	Structure and Function of the Leukocyte Integrin αMβ2
		1 The Multifunctional Integrin Receptor αMβ2
		2 The Structure of the αMβ2 Ectodomain
		3 The β2 I-Domain Relays outside-in and inside-out Signaling
		4 The αMβ2 Complexes with C3d and iC3b
		5 Structural Basis for αMβ2 Recognition of Platelet GPIbα
		6 Recognition of FcgRIIA Sialic Acid by the αI Domain
		7 Structural Aspects of a Lupus Associated αM Variant
		8 Function Modulating Molecules Targeting αMβ2
		9 The Small Molecule αMβ2 Agonist Leukadherin
		10 Discussion and Conclusions
			10.1 Fundamental Principles αM Ligand Recognition
			10.2 Structures of the αMβ2 Heterodimer
		References
Part IV: Integrins in Hemostasis and Immune Control
	Platelet Integrins: Critical Mediators of Haemostasis and Pathological Thrombus Formation
		1 Introduction
		2 Platelets in Thrombosis and Haemostasis
		3 The Physiological Function of Platelet Integrins
			3.1 Integrin αIIbβ3: The Central Integrin for Stable Thrombus Formation
			3.2 Integrin αvβ3: The Vitronectin Receptor
			3.3 Integrin α2β1: A Collagen Receptor
			3.4 Integrins α5β1: The Fibronectin Receptor
			3.5 Integrin α6β1: The Laminin Receptor
		4 Inside-Out Activation of Integrins
			4.1 Upstream Signalling Pathways
			4.2 Rap1: The Master Switch in Platelet Integrin Activation
			4.3 Talin-1 and kindlin-3: Essential Adaptor Proteins for Platelet Integrin Activation
		5 Integrin Outside-In Signalling
			5.1 Events at the β Integrin´s C-Terminus
			5.2 Downstream Signalling Cascades
			5.3 Transmembrane Proteins
		6 Therapeutic Targeting of Integrins
		7 Integrins Beyond Thrombosis and Haemostasis
		8 Conclusions and Future Perspectives
		References
	Integrins as Receptors for Bacterial and Viral Pathogens
		1 Introduction
			1.1 Integrin-Mediated Cell Functions
			1.2 Fundamental Role of Integrins in Microbial Pathogenesis
		2 Pathogen Interactions with Integrins
			2.1 Direct Binding to Integrins
				2.1.1 On Professional Phagocytic Cells
				2.1.2 On Non-Phagocytic Cells
			2.2 Indirect Binding Via Extracellular Matrix Proteins
			2.3 Pathogen-Mediated Degradation of ECM Proteins
		3 Selected Examples of Bacteria- and Virus-Triggered Integrin-Mediated Pathogenic Processes
			3.1 Staphylococcus aureus
				3.1.1 Fibronectin-Integrin Interactions
				3.1.2 Collagen-Integrin Interactions
				3.1.3 Fibrinogen-Staphylococcal MSCRAMM Interactions
			3.2 Streptococcus spp.
			3.3 Yersinia spp.
				3.3.1 Direct Interaction of Invasin (InvA) with β1-Integrins
				3.3.2 Indirect Interaction of YadA and Ail via ECM Molecules with β1-Integrins
			3.4 Human Immunodeficiency Virus (HIV)
			3.5 Influenza Virus
			3.6 Corona Virus SARS-CoV-2
		4 Concluding Remarks
		References