Critical Role of Mast Cell Chymase in Mouse Abdominal Aortic Aneurysm Formation

Sun, Jiusong; Zhang, Jie; Lindholt, Jes Sanddal; Sukhova, Galina K.; Liu, Jian; He, Aina; Åbrink, Magnus; Pejler, Gunnar; Stevens, Richard Lee; Thompson, Robert W.; Ennis, Terri L.; Gurish, Michael F.; Libby, Peter; Shi, Guo‐Ping

doi:10.1161/circulationaha.109.849679

Cited by 134 publications

(151 citation statements)

References 40 publications

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“…Altogether, these data indicate that MCs and MCPT4 can regulate the early inflammatory phase but not the fibrotic phase in this lung injury model. In agreement with the proinflammatory role for MCPT4 in this model, MCPT4 has been shown to play deleterious effects in models of abdominal aortic aneurysm (49), glomerulonephritis (50), or arthritis (51). However, recent evidence also indicates that MCPT4 can have protective functions.…”

Section: Discussionsupporting

confidence: 79%

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

Reber

Daubeuf

Pejler

et al. 2014

The Journal of Immunology

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Mast cells (MCs) are found in large numbers in lungs of patients with pulmonary fibrosis. However, the functions of MCs in lung fibrosis remain largely unknown. We assessed the role of MCs and MC protease 4 (MCPT4), the mouse counterpart of human MC chymase, in a mouse model of bleomycin (BLM)-induced lung injury. We found that levels of inflammation in the bronchoalveolar lavage and the lung, as well as levels of lung fibrosis, were reduced 7 d after intranasal delivery of BLM MC-deficient KitW-sh/W-sh mice compared with wild-type (WT) mice. Confirming the implication of MCs in these processes, we report that the levels of inflammation and fibrosis observed in KitW-sh/W-sh mice can be restored to those observed in WT mice after the adoptive transfer of bone marrow–derived cultured MCs into KitW-sh/W-sh mice. Additionally, we show that levels of inflammation and fibrosis are also reduced in MC chymase MCPT4-deficient mice as compared with WT mice at day 7, suggesting a role for MC-derived MCPT4 in these processes. Our results support the conclusion that MCs can contribute to the initial lung injury induced by BLM through release of the MCPT4 chymase.

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Section: Discussionsupporting

confidence: 79%

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

Reber

Daubeuf

Pejler

et al. 2014

The Journal of Immunology

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“…Other mechanisms may be more important than IgE -for example, inflammatory cytokines from macrophages, MCs, lymphocytes, or other inflammatory cells may induce vascular cell pathologic gene expression (51). Inflammatory cytokines (52), cathepsins (53), and MC proteases (54) in atherosclerotic lesions may also cause vascular cell apoptosis. Therefore, IgE may participate in EC and SMC inflammatory responses, but its importance and significance remain to be evaluated with more in vivo experiments.…”

Section: Figurementioning

confidence: 99%

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

et al. 2011

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IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophagerich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na + /H + exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.

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“…Chymase plays a role in Trichinella spiralis clearance (62) and bacterial infection (63) and has been implicated as a biomarker for cardiovascular diseases (64). CPA regulates sepsis (65) and functions in degrading certain snake venom toxins (65,66).…”

Section: Discussionmentioning

confidence: 99%

Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

Anower-E-Khuda

Habuchi

Nagai

et al. 2013

Journal of Biological Chemistry

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Background: Heparin regulates mast cell proteases. Results: Both HS6ST-1 and HS6ST-2 are involved in 6-O-sulfation of heparin. The contents of tryptase and CPA in mast cells depend on 6-O-sulfation of heparin but chymase does not. Conclusion:The 6-O-sulfation pattern regulates differently the storage of MC-specific proteases. Significance: The fine structure of heparin may be essential for MC homeostasis.

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Critical Role of Mast Cell Chymase in Mouse Abdominal Aortic Aneurysm Formation

Cited by 134 publications

References 40 publications

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe–/– mice

Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

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