Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals

Borchert, Tobias; Beitar, Laura; Langer, LB; Polyák, András; Wester, Hans‐Jürgen; Roß, Tobias L.; Hilfiker‐Kleiner, Denise; Bengel, Frank M.; Thackeray, James T.

doi:10.1007/s12350-019-01929-z

Cited by 38 publications

(31 citation statements)

References 41 publications

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“…However, our immunostaining experiments demonstrate colocalization of TSPO with peripheral macrophages and microglia but not astrocytes in the acute phase, supporting specificity for inflammatory cells. This is consistent with experience in cell culture uptake assays [40]. Immunostaining of heart failure remote myocardium also suggests localization to mitochondria in cardiomyocytes, which aligns with the regulation of TSPO in heart failure [21].…”

Section: Brain (%Id/g) Mi+3d Brain (%Id/g) Mi+8wksupporting

confidence: 87%

Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation

Borchert

Hess

Lukacevic

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI. Methods C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage-and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology. Results Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation. Conclusions Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

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Section: Brain (%Id/g) Mi+3d Brain (%Id/g) Mi+8wksupporting

confidence: 87%

Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation

Borchert

Hess

Lukacevic

et al. 2020

Eur J Nucl Med Mol Imaging

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“…This state of early macrophage activation is necessary for the production of antimicrobial and proinflammatory molecules, which will attempt to clear the infection and promote granuloma formation in order to prevent dissemination of the mycobacteria (Ankrah et al, 2016;Shi et al, 2019). Granulomas consist of macrophages, lymphocytes, neutrophils, and fibroblasts, which may demonstrate some degree of 18 F-FDG uptake as well (Borchert et al, 2019).…”

Section: Pathophysiology Of Tb Infection and Mechanisms Of 18 F-fdg Umentioning

confidence: 99%

Towards more accurate 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in active and latent tuberculosis

Priftakis¹,

Riaz²,

Zumla³

et al. 2020

International Journal of Infectious Diseases

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(TB) is one of the leading causes of death worldwide. Although the disease is curable and preventable, it is underdiagnosed in many parts of the world. Positron emission tomography (PET) imaging using 18 F-FDG in TB can localise disease sites and the extent of disease. 18 F-FDG accumulates in the immune cells that participate in inflammation and granuloma formation, such as activated macrophages and lymphocytes. Therefore, FDG PET/CT scanning is now being evaluated for its usefulness in the diagnosis of extrapulmonary TB and in monitoring the response to treatment. FDG PET/CT imaging is positive and has high sensitivity in active TB, complementing conventional radiological imaging (X-ray, computed tomography, magnetic resonance imaging) in the diagnosis of primary pulmonary, extrapulmonary, and post-primary or miliary TB. FDG PET/CT has low specificity when it is used for solitary pulmonary nodule characterization, and its ability to differentiate TB from malignancy is limited in this setting. Dual point imaging has been proposed as a way to overcome this limitation. FDG PET/CT can reliably differentiate active from inactive disease, and there is promising evidence that it can contribute to the assessment of the response to treatment with an impact on patient management. FDG PET/CT has been found positive in cases of latent TB infection and its ability to identify activation early is currently being explored. More studies are needed to establish the utility of this method in recognizing multidrug-resistant TB cases. Furthermore, other PET radiotracers might prove useful in the functional imaging of TB infection in the future.

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“…However, the true selectively of many of these PET tracers for individual inflammatory cell types remains unknown. While important insights have been gained by studies attempting to answer this question using in vitro cell lines [78], ex vivo histological comparisons, and gene expression data to validate imaging findings, none of these experimental conditions can accurately replicate the in vivo environment. This is an important hurdle for future research in the field, which may be helped by advances in genomic methods such as single cell RNA sequencing and spatial transcriptomics.…”

Section: Targeting Specific Components Of the Immune Responsementioning

confidence: 99%

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation

et al. 2020

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Purpose of Review To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field. Recent Findings While PET imaging with 18F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Summary Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases.

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Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals

Cited by 38 publications

References 41 publications

Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation

Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation

Towards more accurate 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in active and latent tuberculosis

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation

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