Mapping immune processes in intact tissues at cellular resolution

Brede, Christian; Friedrich, Mike; Jordán-Garrote, Ana-Laura; Riedel, Simone S.; Bäuerlein, Carina A.; Heinze, Katrin G.; Bopp, Tobias; Schulz, Stephan; Mottok, Anja; Kiesel, Carolin; Martini, Katharina; Ritz, Miriam; Krosigk, Viktoria von; Rosenwald, Andreas; Einsele, Hermann; Negrin, Robert S.; Harms, Gregory S.; Beilhack, Andreas

doi:10.1172/jci65100

Cited by 35 publications

(37 citation statements)

References 31 publications

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“…To avoid this technical problem, imaging the signals emitted by endogenous fluorophores is an alternative to standard histological preparations for rapid examination of fresh biopsies and has been developed mainly in pathological diagnosis . As observed in other tissues , the intrinsic fluorescence of the inguinal adipose depot clearly showed microanatomical details such as lymph node, main vascularization, and septa between adipocyte clusters (Figure A and supplementary video). Intrinsic fluorescence is a composite signal that is difficult to analyze finely and that includes various putative molecules, located within different cell compartments (NADPH, lipo‐pigments, flavin coenzymes, and so forth) .…”

Section: Discussionmentioning

confidence: 99%

Regionalization of browning revealed by whole subcutaneous adipose tissue imaging

Barreau

Labit

Guissard

et al. 2016

Obesity

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Objective: White and brown adipose tissues play a major role in the regulation of metabolic functions. With the explosion of obesity and metabolic disorders, the interest in adipocyte biology is growing constantly. While several studies have demonstrated functional differences between adipose fat pads, especially in their involvement in metabolic diseases, there are no data available on possible heterogeneity within an adipose depot. Methods: This study investigated the three-dimensional (3-D) organization of the inguinal fat pad in adult mice by combining adipose tissue clearing and autofluorescence signal acquisition by confocal microscopy. In addition, the study analyzed the expression of genes involved in adipocyte biology and browning at the mARN and protein levels in distinct areas of the inguinal adipose tissue, in control conditions and after cold exposure. Results: Semiautomated 3-D image analysis revealed an organization of the fat depot showing two regions: the core was structured into segmented lobules, whereas the periphery appeared unsegmented. Perilipin immunostaining showed that most of the adipocytes located in the core region had smaller lipid droplets, suggesting a brown-like phenotype. qPCR analysis showed a higher expression of the browning markers Ucp1, Prdm16, Ppargc1a, and Cidea in the core region than at the periphery. Finally, cold exposure induced upregulation of thermogenic gene expression associated with an increase of UCP1 protein, specifically in the core region of the inguinal fat depot. Conclusions:Altogether, these data demonstrate a structural and functional heterogeneity of the inguinal fat pad, with an anatomically restricted browning process in the core area.

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Section: Discussionmentioning

confidence: 99%

Regionalization of browning revealed by whole subcutaneous adipose tissue imaging

Barreau

Labit

Guissard

et al. 2016

Obesity

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“…Light-sheet field microscopy was performed as previously described (69). Briefly, PFA-fixed organs were dehydrated with increasing concentrations of ethanol and cleared with benzyl benzoate to benzyl alcohol at a 2: ratio.…”

Section: Methodsmentioning

confidence: 99%

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

et al. 2018

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The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity.

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“…Next, cells were stained using the following fluorescently labeled antibodies (in different combinations): anti-CD3e (clone 145-2c11), anti-CD4 (clone RM4-5), anti-CD8 (clone 53-6.7), anti-CD11b (clone Light-Sheet Microscopy. Light-sheet fluorescence microscopy (LSFM) was performed for cardiac samples according to protocols previously established by Heinze and coworkers (59). Briefly, excised hearts were perfused with PBS and then 4% (wt/vol) formaldehyde in PBS via the aorta.…”

Section: Methodsmentioning

confidence: 99%

Myocardial aging as a T-cell–mediated phenomenon

Ramos

Berg²,

Silva

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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142

117

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In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissueresident leukocytes and with an accumulation of activated CD4 + Foxp3 − (forkhead box P3) IFN-γ + T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.T he myocardial cellular composition has been revisited in recent years, and leukocyte subsets residing in the healthy heart have been described (1-10). Cardiac-resident macrophages exhibiting an M2-like gene expression profile were found to be distributed in close association with the coronary vascular bed (3), and niches for dendritic cells (CD11c + MHC-II high CD80/86 low ) were found near the cardiac valves of the intact heart (1). It was also demonstrated that cardiac-resident MHCII + cells process and present myosin heavy chain-alpha-derived peptides under steady-state conditions (11, 12) and prime T cells ex vivo (1). However, whether lymphocytes can seed the intact myocardium and whether T-cell priming with myocardial antigens can occur in the absence of an infection or autoimmune myocarditis remain elusive.More recently, accumulating evidence indicated that noninfectious myocardial diseases are modulated by T cells. During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13-16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20). However, these autoreactive T cells can also b...

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Mapping immune processes in intact tissues at cellular resolution

Cited by 35 publications

References 31 publications

Regionalization of browning revealed by whole subcutaneous adipose tissue imaging

Regionalization of browning revealed by whole subcutaneous adipose tissue imaging

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Myocardial aging as a T-cell–mediated phenomenon

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