Early Phase Mast Cell Activation Determines the Chronic Outcome of Renal Ischemia–Reperfusion Injury

Danelli, Luca; Madjène, Lydia Celia; Madera-Salcedo, Iris K.; Gautier, Grégory; Pacreau, Emeline; Mkaddem, Sanae Ben; Charles, Nicolas; Daugas, Éric; Launay, Pierre; Blank, Ulrich

doi:10.4049/jimmunol.1601282

Cited by 31 publications

(28 citation statements)

References 59 publications

(69 reference statements)

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“…We have also analyzed possible cytokines involved in this transition such as TGFβ (41) and IL6 (40). We found that stimulation of cultured MCs via the IgE receptor can induce the production of these cytokines in agreement with previously published data (47, 58). …”

Section: Discussionsupporting

confidence: 93%

“…These results add to a series of studies showing on the role of MC in fibrosis development. While some reported that MC promote fibrosis development (22, 44, 46, 47) as shown here, others suggested that MC or derived mediators can have a protective role (14, 19). These differences may be explained by the specific pathophysiological context with different types of injuries but also disease kinetics.…”

Section: Discussionmentioning

confidence: 50%

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Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction

et al. 2017

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Obstructive nephropathy constitutes a major cause of pediatric renal progressive disease. The mechanisms leading to disease progression are still poorly understood. Kidney fibrotic lesions are reproduced using a model of partial unilateral ureteral obstruction (pUUO) in newborn mice. Based on data showing significant mast cell (MC) infiltration in patients, we investigated the role of MC and murine MCPT4, a MC-released chymase, in pUUO using MC- (Wsh/sh), MCPT4-deficient (Mcpt4−/−), and wild-type (WT) mice. Measurement of kidney length and volume by magnetic resonance imaging (MRI) as well as postmortem kidney weight revealed hypotrophy of operated right kidneys (RKs) and compensatory hypertrophy of left kidneys. Differences between kidneys were major for WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− mice. Fibrosis development was focal and increased only in WT-obstructed kidneys. No differences were noticed for local inflammatory responses, but serum CCL2 was significantly higher in WT versus Mcpt4−/− and Wsh/sh mice. Alpha-smooth muscle actin (αSMA) expression, a marker of epithelial–mesenchymal transition (EMT), was high in WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− RK. Supernatants of activated MC induced αSMA in co-culture experiments with proximal tubular epithelial cells. Our results support a role of MC in EMT and parenchyma lesions after pUUO involving, at least partly, MCPT4 chymase. They confirm the importance of morphologic impairment evaluation by MRI in pUUO.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 50%

Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction

et al. 2017

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“…However, detection of MC‐tryptase in renal draining LNs of mice with glomerulonephritis has been described . In addition, murine MCs expressing connectival‐like proteases such as MCPT‐6 and MCPT‐4 have been described to localize in the renal capsules, where they showed pattern of degranulation in the setting of renal inflammation . Although the number of reports studying MC activation in experimental models of renal diseases is increasing, the knowledge about the involved mediators is still limited.…”

Section: Kidney Mast Cellssupporting

confidence: 65%

“…Using MC‐deficient mice, several animal models of renal diseases have revealed a more complex scenario, with both aggravating and protective roles of the MC, depending on the experimental model but also on the employed MC‐deficient mouse strain . MCs are virtually absent in the parenchyma of mouse kidneys but, in contrast with human chronic diseases, they have not been found infiltrating fibrotic kidneys in different models . In rats, several reports suggested that renal fibrosis instauration is accompanied by MC infiltration .…”

Section: Kidney Mast Cellsmentioning

confidence: 98%

Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity?

Frossi

Mion

Sibilano

et al. 2018

Immunological Reviews

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Mast cells (MCs) are derived from committed precursors that leave the hematopoietic tissue, migrate in the blood, and colonize peripheral tissues where they terminally differentiate under microenvironment stimuli. They are distributed in almost all vascularized tissues where they act both as immune effectors and housekeeping cells, contributing to tissue homeostasis. Historically, MCs were classified into 2 subtypes, according to tryptic enzymes expression. However, MCs display a striking heterogeneity that reflects a complex interplay between different microenvironmental signals delivered by various tissues, and a differentiation program that decides their identity. Moreover, tissue-specific MCs show a trained memory, which contributes to shape their function in a specific microenvironment. In this review, we summarize the current state of our understanding of MC heterogeneity that reflects their different tissue experiences. We describe the discovery of unique cell molecules that can be used to distinguish specific MC subsets in vivo, and discuss how the improved ability to recognize these subsets provided new insights into the biology of MCs. These recent advances will be helpful for the understanding of the specific role of individual MC subsets in the control of tissue homeostasis, and in the regulation of pathological conditions such as infection, autoimmunity, and cancer.

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“…Consistent with an important role for mast cells in kidney injury, a recent study showed that mast cell ablation in the early phases of renal injury is sufficient to reduce subsequent fibrosis by decreasing the inflammatory response. 27,28 Activation of Epithelial, Endothelial, and Stromal Cells in Allograft Rejection We next compared epithelial transcriptomes from the biopsy with their healthy counterparts. Multiple attempts at scRNAseq of healthy nephrectomy tissue failed to generate libraries; however, we were successful in generating adult human kidney single-nucleus RNA-sequencing (RNA-seq) data.…”

Section: Comparative Analysis Reveals Monocyte Cell-state Transition mentioning

confidence: 99%

Single-Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response

Wu¹,

Malone²,

Donnelly³

et al. 2018

JASN

331

315

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Single-cell genomics techniques are revolutionizing our ability to characterize complex tissues. By contrast, the techniques used to analyze renal biopsy specimens have changed little over several decades. We tested the hypothesis that single-cell RNA-sequencing can comprehensively describe cell types and states in a human kidney biopsy specimen. We generated 8746 single-cell transcriptomes from a healthy adult kidney and a single kidney transplant biopsy core by single-cell RNA-sequencing. Unsupervised clustering analysis of the biopsy specimen was performed to identify 16 distinct cell types, including all of the major immune cell types and most native kidney cell types, in this biopsy specimen, for which the histologic read was mixed rejection. Monocytes formed two subclusters representing a nonclassical CD16+ group and a classic CD16- group expressing dendritic cell maturation markers. The presence of both monocyte cell subtypes was validated by staining of independent transplant biopsy specimens. Comparison of healthy kidney epithelial transcriptomes with biopsy specimen counterparts identified novel segment-specific proinflammatory responses in rejection. Endothelial cells formed three distinct subclusters: resting cells and two activated endothelial cell groups. One activated endothelial cell group expressed Fc receptor pathway activation and Ig internalization genes, consistent with the pathologic diagnosis of antibody-mediated rejection. We mapped previously defined genes that associate with rejection outcomes to single cell types and generated a searchable online gene expression database. We present the first step toward incorporation of single-cell transcriptomics into kidney biopsy specimen interpretation, describe a heterogeneous immune response in mixed rejection, and provide a searchable resource for the scientific community.

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Early Phase Mast Cell Activation Determines the Chronic Outcome of Renal Ischemia–Reperfusion Injury

Cited by 31 publications

References 59 publications

Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction

Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction

Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity?

Single-Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response

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