Imaging Inflammation

Description:
Imaging Inflammation provides updates on cutting-edge imaging methods being applied to problems in inflammation research. From state-of-the-art research tools to diagnostic tests, and from single-cell to whole-body imaging, this volume offers a comprehensive overview of how imaging experts across a range of disciplines are expanding our understanding of inflammation and immunity.

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Preface

We are no longer entirely reliant on assessments of redness, swelling and exudate to identify inflammation by sight—many techniques are now available for molecular imaging of inflammatory responses. New imaging techniques are rapidly being adopted for use in immunology research, and these methods rarely completely supersede existing approaches. This leaves those of us interested in imaging inflammatory responses with a complex choice of which imaging method or methods to use for solving the problem at hand.

We compiled this volume to give researchers interested in the biology of inflammation and immunity a broad guide to some of the imaging techniques that are likely most useful for use in answering their research questions. The readers will find in each chapter of Imaging Inflammation a brief introduction to the technical aspects of the respective imaging modalities, followed by examples and discussions of their application in inflammation research.

Imaging Inflammation begins with a historical perspective on imaging on immune responses from Doreen Lau, taking us on a journey from the first observations of living cells by Antonie van Leeuwenhoek to non-invasive whole-body imaging of immune cells by positron emission tomography.

The book chapters then follow an approximate scale that starts from the largest field of view, with whole-body molecular imaging modalities, and progressively narrows down to high-resolution techniques which enable spatial visualisation of gene transcription patterns.

Nuclear imaging modalities are addressed by George Keeling and Francis Man, beginning with brief descriptions of the principles of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) and the various structural classes of radiotracers. This chapter provides an overview of the use of nuclear imaging for the detection and monitoring of inflammatory diseases in patients. It then covers molecular processes involved in inflammation that have more recently become imaging targets and are mostly at the preclinical research stage, including amino acid transporters, fibroblast activation protein and markers of specific subsets of immune cells.

Magnetic resonance imaging (MRI) is another imaging modality that allows whole-body imaging as well as more organ-focused imaging. Here, Vanessa Johanssen, Niloufar Zarghami and Nicola Sibson provide their insights on MRI of neuroinflammation, with a focus on use of magnetic iron nanoparticles targeted towards markers of vascular inflammation and immune cell activation.

Matthew Muller, Jonathan Lindner and Matthew Hagen offer the reader their perspective of ultrasound imaging, using for example B-mode, Doppler, and contrast-enhanced ultrasound to explore rheumatoid arthritis, atherosclerosis and myocardial ischaemia. They demonstrate how targeted microbubbles can enable imaging of specific molecular processes non-invasively, using low-cost handheld probes.

Optical imaging is a modality crossing through a range of scales and can be used for whole-body imaging, tissue-level and subcellular imaging. In their chapter, Jen-Chieh Tseng and Jeffrey Peterson describe the use of chemiluminescence and near-infrared fluorescence for whole-body imaging of inflammation. In particular, they explore the use of reactive probes that emit light in response to the production of reactive oxygen species in inflamed tissues, as well as activatable probes that contain peptide sequences uniquely cleaved by inflammatory proteases such as cathepsins. Perhaps less well known but no less fascinating is the possibility of 3D in vivo fluorescence imaging, which is also briefly covered.

Photoacoustic imaging is a relatively recent imaging modality that combines an optical input signal with an ultrasonic output, combining advantages of both techniques. In this chapter by Jingqin Chen, Zhihua Xie, Liang Song, Xiaojing Gong and Chengbo Liu, readers can learn about label-free photoacoustic imaging of endogenous molecules, such as haemoglobin, and activatable probes that respond to changes in the inflammatory microenvironment. An interesting feature of photoacoustic imaging is its ability to image at different scales depending on instrument configuration, ranging from photoacoustic microscopy that images at high resolutions (a few microns laterally) but limited depths (a few millimetres) to photoacoustic tomography that can image tissues several centimetres deep but at more modest spatial resolution (a few hundred microns). The optical component also enables multispectral imaging, meaning that probes and endogenous molecules that absorb at different wavelengths can be imaged simultaneously and discriminated. This allows multiple inflammatory processes to be captured concomitantly.

Marco De Donatis, Frédéric Fercoq and Leo Carlin explore the use of intravital microscopy to image inflammation in living tissues, tracking single cells as they migrate between blood vessels and organs. In particular, they highlight how intravital microscopy allows the study of systems that are difficult to model in vitro because of their complexity, such as host–parasite interactions and viral infections. This chapter gives an update on the latest intravital microscopy approaches, which allow imaging of multiple markers at the same time with high temporal and spatial resolution. These features allow precise determination of cell migration, plasma extravasation and tissue remodelling in live tissues.

Finally, Kenneth Hu takes the reader to the frontier where imaging meets transcriptomics, describing how the spatial organisation of tissues can be mappedwith the low bias and high dimensionality offered by mRNA sequencing. With spatial transcriptomic techniques such as multiplexed fluorescent in situ hybridisation, Slide-seq and ZipSeq, analysis is no longer limited to single-digit numbers of targets per sample and transcriptomes can be related to their locations of expression.

Some emerging approaches for imaging that we think will be of future interest to immunologists are not yet covered in this series. These methods include imaging mass spectrometry, imaging mass cytometry, techniques for immunofluorescence imaging of many proteins in the same sample including histo-cytometry, electron and super-resolution microscopy approaches, lattice light sheet imaging and tissue clearing and expansion approaches for sample preparation.

We would like to stress is that there is no ‘magic bullet’ imaging modality combining the ideal characteristics of a whole-body field-of-view with high spatiotemporal resolution, high sensitivity, unlimited depth of penetration, unbiased imaging of all molecular contents of samples, zero toxicity and low cost. To efficiently advance our fields, it is therefore imperative on us as researchers to choose the techniques we use for our problems wisely and to work on improving methods for continuing progress in inflammation research and beyond.

London, UK Francis Man San Francisco, CA, USA Simon J. Cleary

Table of contents :
Preface
Acknowledgements
Contents
About the Editors
Imaging Inflammation: A Historical Perspective
1 Microscopy for Imaging Inflammation: The Germ Theory
2 Imaging Leukocyte Function in Humoral and Cell-Mediated Immunity
3 The Dawn of Radiology and Noninvasive Imaging of Inflammation
4 Conclusion
References
Nuclear Imaging of Inflammation
1 Introduction to Nuclear Imaging
1.1 Basic Principles of PET and SPECT
1.2 Benefits and Limitations of Nuclear Imaging
1.3 Radiotracers: Radionuclides, Targeting Moieties, and Practical Considerations
1.3.1 Radionuclides
1.3.2 Radiotracers: Structural Classes
1.3.3 Multimodal and Multi-Tracer Imaging
1.3.4 Practical Considerations for Preclinical Nuclear Imaging of Inflammation
2 Clinical Nuclear Imaging of Inflammation
2.1 Current Uses and Tracers
2.1.1 Inflammation in the Gastrointestinal Tract
2.1.2 Cardiovascular Inflammation
2.1.3 Neuroinflammation
2.1.4 Musculoskeletal Diseases
2.1.5 Fever of Unknown Origin (FUO)
2.1.6 Infection Imaging
2.2 Challenges and Recent Developments
2.2.1 Increasing Specificity
2.2.2 Quantification and Multimodal Imaging
2.2.3 Radiomics
3 Recent Developments in Preclinical Nuclear Imaging of Inflammation
3.1 Metabolic Pathways Involved in Inflammation
3.1.1 Translocator Protein (TSPO) Ligands
3.1.2 Amino Acid Metabolism: LAT1
3.1.3 Folate Receptor β
3.1.4 Imaging Hypoxia
3.1.5 Aldehyde Radiotracers
3.1.6 Radioactive Gallium in the Host-Pathogen Fight over Iron
3.2 Adhesion Molecules and Intercellular Signalling Pathways
3.2.1 Fibroblast Activation Protein (FAP)
3.2.2 Antigen-Presenting Cell Activation Markers: CD80/CD86
3.2.3 Macrophage Activation Marker: Mannose Receptor/CD206
3.2.4 Chemokine Receptors
3.2.5 Cell-Adhesion Molecules (CAMs): Integrins and Selectins
3.2.6 Matrix Metalloproteinases
3.2.7 Radionuclide Imaging of T Cells and B Cells in Inflammation
3.2.8 Vascular Adhesion Protein-1 (VAP-1)
4 Conclusion and Perspectives
References
Magnetic Resonance Imaging of Neuroinflammation
1 Introduction
1.1 MRI
1.2 Molecular MRI
2 Molecular MRI to Reveal Inflammation in the Brain
2.1 Multiple Sclerosis
2.2 Stroke
2.3 Epilepsy
2.4 Brain Cancer
3 Extension of Molecular MRI to Other Diseases and Tissues
4 Future Perspective
5 Conclusions
References
Ultrasound Imaging in Inflammation Research
1 Introduction
1.1 Ultrasound Physics
1.2 Ultrasound Modalities
2 B-Mode and Doppler Ultrasound Imaging of Inflammation
2.1 Renal B-Mode and Doppler Ultrasound Imaging
2.2 Rheumatoid Arthritis Imaging
2.3 Plaque Imaging
3 Contrast-Enhanced Ultrasound (CEU) Molecular Imaging
3.1 CEU Molecular Imaging of Cardiovascular Inflammation
3.1.1 Ischemic Memory
3.1.2 Atherosclerosis
3.2 Organ-Specific Applications of CEU Molecular Imaging
3.3 Limitations and Benefits Compared to Other Molecular Imaging Approaches
4 Conclusion
References
Whole-Body Chemiluminescence and Fluorescence Imaging of Inflammation
1 Introduction and Background
1.1 Significance of Imaging Inflammation in Animal Models
1.2 Unique Cell Biology of Inflammation: Phagocytes
1.3 Unique Inflammatory Enzymes for ROS Production
1.4 Unique Inflammatory Proteases
1.5 Advantages of Whole-Body Optical Imaging for Inflammation Research
1.6 Chemiluminescence Imaging (CLI) and Fluorescence Imaging (FLI): An Overview
2 Imaging Inflammation Using ROS-Sensitive Chemiluminescent Compounds
2.1 Small Chemiluminescent Compounds
2.2 Energy Transfer Luminescence Imaging Using Small CLI Substrates as Energy Sources
3 Noninvasive Fluorescence Imaging for Tissue Inflammation
3.1 Targeting Enhanced Vascular Permeability at Inflamed Sites
3.2 Selective Binding and Targeting of Inflammatory Protein Markers
3.3 ROS-Reactive Fluorescent Probes for Inflammation Imaging
3.4 Activatable Fluorescent Probes for Imaging Specific Inflammatory Protease Activity
4 Conclusion
References
Photoacoustic Imaging in Inflammation Research
1 Introduction to Photoacoustic Imaging
2 Label-Free Photoacoustic Imaging of Inflammation
2.1 Evaluation of Inflammation by Photoacoustic Imaging of Hemoglobin
2.2 Label-Free Photoacoustic Imaging of Blood Oxygen Saturation and Collagen in Crohn´s Disease
3 Probe-Based Photoacoustic Imaging of Inflammation
3.1 Activatable Photoacoustic Probes Responsive to Inflammatory Stimuli
3.1.1 Reactive Oxygen Species (ROS)-Responsive Probes
3.1.2 Reactive Oxygen Species/Glutathione-Responsive Probes
3.1.3 Carbon Monoxide-Responsive Probes
3.1.4 Leukotriene A4 Hydrolase-Responsive Probes
3.2 Photoacoustic Probe Targeted Toward Inflammation Markers
3.2.1 Photoacoustic Probes Targeted Toward CD36
3.2.2 Photoacoustic Imaging of Arthritis Based on an IL-6 Targeted Probe
3.3 Direct Labeling of Immune Cells for Photoacoustic Imaging of Inflammation
4 Conclusion and Prospects of Photoacoustic Imaging in Inflammation Research
References
Imaging Inflammation by Intravital Microscopy
1 Introduction
2 Leukocyte Migration to the Site of Inflammation: Imaging Trafficking in Intravascular (and Non-vascular) Spaces
2.1 Imaging Classical Leukocyte Rolling and Firm Adhesion
2.2 Imaging Novel Leukocyte Trafficking Events
3 Visualising the Inflammatory Response in Sterile Injury, Infection and Cancer
3.1 Imaging Sterile Injury
3.2 Imaging Infection
3.2.1 Bacterial Infections and Bacterial PAMPs
3.2.2 Viral Infection
3.2.3 Parasite Infection
3.3 Imaging the Tumour Microenvironment: Inflammation in Cancer
4 Conclusion and Future Perspectives
References
Spatial Transcriptomics in Inflammation: Dissecting the Immune Response in 3D in Complex Tissues
1 The Importance of Spatial Dimensions When Studying Immune Responses in Tissue
1.1 Lymphoid Tissues: It´s All About Space
1.2 Spatial Organization of Immune Cells in Nonlymphoid Tissues Is Vital to Their Function
1.3 Immune Cells in the Physical Space of the Tumor: Order from Chaos
1.4 Spatial Aspects of Autoimmunity
1.5 Summary: Capturing Spatial Information is Vital for Understanding Immunity
2 The Spatial Transcriptomic Toolbox
2.1 The Ever-Evolving Spatial Transcriptomic Toolbox
2.1.1 Targeted Approaches
2.1.2 “Whole´´ or “Untargeted´´ Transcriptome Capture Techniques
Solid-Phase Capture
Region-Based Selection
Combining Grids with “True´´ Single-Cell Transcriptomics
2.2 Parameters to Consider
2.2.1 Targeted Versus Untargeted Approaches
2.2.2 Lost in Reverse Transcription: Transcriptome Capture Efficiency
2.2.3 Spatial Resolution: How Low Can We Go?
2.2.4 What Kind of Samples Can We Use?
3 What Has Been Done with Spatial Transcriptomics in Studying Immunology?
3.1 Skin Wound Healing
3.2 The Tumor Microenvironment
3.3 Lymphoid Tissues
3.4 Infectious Disease and Autoimmunity
4 We Have Our Data, Now What? How Do We Analyze Spatial Transcriptomic Data? And Where Can We Go from Here?
4.1 Deconvolving Spatial Transcriptomes
4.2 Extracting Cell-Cell Communication
4.3 Building a Spatial Compendium of Tumors
4.4 Spatial Transcriptomics Applied to Organoids
5 Conclusion
References