The Inflammatory Response after an Epidermal Burn Depends on the Activities of Mouse Mast Cell Proteases 4 and 5

Younan, George; Suber, Freeman; Xing, Wei; Shi, Tao; Kunori, Yuichi; Åbrink, Magnus; Pejler, Gunnar; Schlenner, Susan; Rodewald, Hans Reimer; Moore, Francis D.; Stevens, Richard L; Adachi, Roberto; Austen, K. Frank; Gurish, Michael F.

doi:10.4049/jimmunol.1002803

Cited by 68 publications

(69 citation statements)

References 52 publications

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“…Earlier studies have shown that mMCP-4, -5, -6 and MC-CPA are strictly dependent on serglycin for their storage in secretory granules (Henningsson et al , 2002 ;Å brink et al, 2004 ;Henningsson et al , 2006 ), and here we demonstrate the absence of these proteases in serglycin −/− PCMCs ( Figure 1C). Genetic deficiency of either mMCP-4 or mMCP-6 did not substantially affect levels of other MC proteases in PCMCs, whereas MC-CPA-deficiency was accompanied by a total lack of mMCP-5, as expected due to the known interdependency of these proteases for proper storage (Feyerabend et al , 2005 ;Younan et al , 2010 ). Normal morphology and staining properties were seen in PCMCs derived from mMCP-4 −/− , mMCP-6 −/− , MC-CPA −/− and MC-CPAmut (mice with an inactivating mutation in the active site of MC-CPA) ( Figure 1A).…”

Section: Phenotype Of Cultured Peritoneal Mcsmentioning

confidence: 55%

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Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

Waern

Karlsson

Thorpe

et al. 2012

Biological Chemistry

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: Mast cell (MC) granules contain large amounts of proteases of the chymase, tryptase and carboxypeptidase A (MC-CPA) type that are stored in complex with serglycin, a proteoglycan with heparin side chains. Hence, serglycinprotease complexes are released upon MC degranulation and may influence local inflammation. Here we explored the possibility that a serglycin-protease axis may regulate levels of IL-13, a cytokine involved in allergic asthma. Indeed, we found that wild-type MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation, whereas serglycin −/− MCs completely lacked this ability. Moreover, MC-mediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist, which suggests that IL-13 degradation is catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation is dependent on both the serglycin and the protease component of the serglycin-protease complex. Moreover, IL-13 degradation was abrogated in MC-CPA −/− MC cultures, but was normal in cultures of MCs with an inactivating mutation of MC-CPA, which suggests that the IL-13-degrading serine proteases rely on MC-CPA protein. Together, our data implicate a serglycin-serine protease axis in the regulation of extracellular levels of IL-13. Reduction of IL-13 levels through this mechanism possibly can provide a protective function in the context of allergic inflammation.

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Section: Phenotype Of Cultured Peritoneal Mcsmentioning

confidence: 55%

“…This, together with the known dependence of mMCP-5 on serglycin for storage (Younan et al , 2010 ), strongly implicated mMCP-5 (or other MC-CPA-dependent proteases) in the degradation of IL-13 by activated MCs. We therefore assessed the capacity of recombinant mMCP-5 to degrade IL-13.…”

Section: Recombinant Mmcp-5 Does Not Reconstitute Il-13 Degradation Bmentioning

confidence: 89%

Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

Waern

Karlsson

Thorpe

et al. 2012

Biological Chemistry

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“…Chymase has been demonstrated to induce the proliferation of cardiac fibroblasts, and to have important roles in the development of fibrosis in the lungs and heart via angiotensin II (21,22). Angiotensin II is an important growth factor in the renin-angiotensin system.…”

Section: Discussionmentioning

confidence: 99%

Mast cell chymase promotes hypertrophic scar fibroblast proliferation and collagen synthesis by activating TGF‑β1/Smads signaling pathway

Chen

Yang

et al. 2017

Exp Ther Med

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Abstract. The present study assessed the existence of mast cell chymase in hypertrophic scars and determined whether chymase promotes fibrosis via the transforming growth factor (TGF)-β1/Smads signaling pathway. Five patients with hypertrophic scars and another five patients subjected to repair and reconstruction of other tissue defects were included in the present study. To detect the existence of mast cells and mast cell chymase in hypertrophic scars, immunohistochemistry was employed. To test the effect of chymase on TGF-β1, angiotensin, and type I and III collagen mRNA expression in isolated hypertrophic scar fibroblasts in vitro, reverse-transcription quantitative PCR was performed. To investigate how chymase affects TGF-β1, phosphorylated (P)-Smad2/3 as well as Smad4 and Smad7 protein expression, western blot analysis was used. Mast cell chymase was identified to promote the mRNA expression of TGF-β1, angiotensin, and type I and III collagen in hypertrophic scar fibroblasts in a time-and dose-dependent manner. Furthermore, treatment with 60 ng/ml mast cell chymase for 12 h led to the upregulation of TGF-β1, P-Smad2/3, Smad4 and Smad7 in hypertrophic scar fibroblasts. The present study demonstrated that mast cells and chymase are present in hypertrophic scars, and chymase promotes hypertrophic scar fibroblast proliferation and collagen synthesis by activating the TGF-β1/Smads signaling pathway.

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“…By mass spectrometry, we found Val and Ala cleavage sites in VIP or helodermin that would be predicted to be susceptible to MCPT5 (which has elastolytic activity) (48) but not to the chymase MCPT4 (47). We previously showed that the absence of MCPT4 in Mcpt4 -/-mice does not result in reduced expression or storage of other mast cell proteases (including MCPT5) (41,49,50). However, to investigate the potential role of MCPT5 in degrading VIP or helodermin, we tested the ability of PMCs from Cpa3-deficient (Cpa3 -/-) mice, which lack both CPA3 and MCPT5 proteins (51), to degrade VIP in vitro.…”

Section: Figurementioning

confidence: 99%

Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice

Akahoshi¹,

Song²,

Piliponsky³

et al. 2011

J. Clin. Invest.

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133

131

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Mast cell degranulation is important in the pathogenesis of anaphylaxis and allergic disorders. Many animal venoms contain components that can induce mast cell degranulation, and this has been thought to contribute to the pathology and mortality caused by envenomation. However, we recently reported evidence that mast cells can enhance the resistance of mice to the venoms of certain snakes and that mouse mast cell-derived carboxypeptidase A3 (CPA3) can contribute to this effect. Here, we investigated whether mast cells can enhance resistance to the venom of the Gila monster, a toxic component of that venom (helodermin), and the structurally similar mammalian peptide, vasoactive intestinal polypeptide (VIP). Using 2 types of mast cell-deficient mice, as well as mice selectively lacking CPA3 activity or the chymase mouse mast cell protease-4 (MCPT4), we found that mast cells and MCPT4, which can degrade helodermin, can enhance host resistance to the toxicity of Gila monster venom. Mast cells and MCPT4 also can limit the toxicity associated with high concentrations of VIP and can reduce the morbidity and mortality induced by venoms from 2 species of scorpions. Our findings support the notion that mast cells can enhance innate defense by degradation of diverse animal toxins and that release of MCPT4, in addition to CPA3, can contribute to this mast cell function.

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The Inflammatory Response after an Epidermal Burn Depends on the Activities of Mouse Mast Cell Proteases 4 and 5

Abstract: Material

Cited by 68 publications

References 52 publications

Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis

Mast cell chymase promotes hypertrophic scar fibroblast proliferation and collagen synthesis by activating TGF‑β1/Smads signaling pathway

Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice

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