Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Scandiuzzi, Lisa; Beghdadi, Walid; Daugas, Éric; Åbrink, Magnus; Tiwari, Neeraj; Brochetta, Cristiana; Claver, Julien; Arouche, Nassim; Zang, Xingxing; Pretolani, Marina; Monteiro, Renato C.; Pejler, Gunnar; Blank, Ulrich

doi:10.4049/jimmunol.0902129

Cited by 63 publications

(74 citation statements)

References 56 publications

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“…Mcpt4 deletion reduces kidney TNFα and MCP1, but not IL1β or TGFβ, mRNA in experimental chronic kidney disease, suggesting that MMCP-4 is proinflammatory (24). We found no significant differences in serum TNFα, MCP1, IL1β, and TGFβ between 72-h post-I/R WT and Mcpt4 −/− mice (Table S6).…”

Section: Mmcp-4 Regulates Cardiac Igf-1 and Igf-1/igf-1r Signaling Pomentioning

confidence: 43%

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

Tejada

Tan

Torres

et al. 2016

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

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Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease.insulin-like growth factor-1 | chymase | mouse mast cell protease 4 | ischemia-reperfusion injury | cardioprotection

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Section: Mmcp-4 Regulates Cardiac Igf-1 and Igf-1/igf-1r Signaling Pomentioning

confidence: 43%

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

Tejada

Tan

Torres

et al. 2016

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

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“…14,15 In addition, mast-cell degranulation can activate or regulate the adaptive immune system. 16 In the kidney, mast cells have been shown to have both inflammatory 17,18 and protective functions. 19 -21 Recent advances examining the role of mast cells in vivo have been facilitated by mice with genetic deletions specific for mast cells.…”

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confidence: 99%

Mast Cells Mediate Acute Kidney Injury through the Production of TNF

Summers

Chan

Gan

et al. 2011

Journal of the American Society of Nephrology

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Leukocyte recruitment contributes to acute kidney injury (AKI), but the mechanisms by which leukocytes promote injury are not completely understood. The degranulation of mast cells releases inflammatory molecules, including TNF, but whether these cells participate in the pathogenesis of AKI is unknown. Here, we induced AKI with cisplatin in mast cell-deficient and wild-type mice. Compared with wild-type mice, deficiency of mast cells attenuated renal injury, reduced serum levels of TNF, and reduced recruitment of leukocytes to the inflamed kidney. Mast cell-deficient mice also exhibited significantly lower intrarenal expression of leukocyte chemoattractants. Mast cell-deficient mice reconstituted with mast cells from wild-type mice exhibited similar cisplastin-induced renal damage and serum levels of TNF as wild-type mice. In contrast, mast cell-deficient mice reconstituted with mast cells from TNF-deficient mice continued to demonstrate significant attenuation of cisplatin-induced renal injury. Furthermore, the mast-cell stabilizer sodium chromoglycate also significantly abrogated renal injury in this model of AKI. Taken together, these results suggest that mast cells mediate AKI through the production of TNF.

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“…MCs have emerged as potential key players in the induction, amplification, and paradoxically immunomodulation of autoimmunity in general and rapidly progressive forms of GN in particular. 2,17,34,35 In MPO-AAV, MCs are a major leukocyte population seen in infiltrating damaged kidneys. Although the functional role of MCs in patients with MPO-AAV is uncertain, the patients with the highest MC density had the most severe tubulointerstitial damage.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Gan

O’Sullivan

Ooi

et al. 2015

JASN

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Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4 + effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV. 27: 132127: -133327: , 201627: . doi: 10.1681 Mast cells (MCs) are best characterized in pathology by their effector roles in IgE-dependent degranulation and by their release of pro-inflammatory mediators in allergy and anaphylaxis. 1 However, it is now recognized that MCs also play important roles in host defense and also in non-allergic inflammatory diseases, particularly those initiated by autoimmunity. The functional diversity of MC phenotypes allows for their participation in the generation of adaptive immune responses, playing either injurious or modulatory roles in many chronic human diseases and animal models of these diseases. 2 A functional role for MCs in a particular human disease can be suspected by confirming MC presence in diseased target organs and demonstrating a correlation between MC activation status and disease outcome. This potential cause and effect association can be strengthened by studies in relevant murine models of the particular diseases comparing disease patterns and outcomes between MC-deficient (Kit Wsh/Wsh ) mice and Kit Wsh/Wsh mice reconstituted with MCs. [2][3][4][5] The mechanistic basis of J Am Soc Nephrol

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Mouse Mast Cell Protease-4 Deteriorates Renal Function by Contributing to Inflammation and Fibrosis in Immune Complex-Mediated Glomerulonephritis

Cited by 63 publications

References 56 publications

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

Mast Cells Mediate Acute Kidney Injury through the Production of TNF

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

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