Mast Cell Chymase Degrades the Alarmins Heat Shock Protein 70, Biglycan, HMGB1, and Interleukin-33 (IL-33) and Limits Danger-induced Inflammation

Roy, Ananya; Ganesh, Goutham V.; Sippola, Helena; Bolin, Sara; Sawesi, Osama; Dagälv, Anders; Schlenner, Susan; Feyerabend, Thorsten B.; Rodewald, Hans Reimer; Kjellén, Lena; Hellman, Lars; Åbrink, Magnus

doi:10.1074/jbc.m112.435156

Cited by 110 publications

(104 citation statements)

References 65 publications

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“…Indeed, MC granules contain a wide range of proteases and mMCP-4, the homolog of the human chymase, has been shown to degrade several alarmins, including IL33, both in vitro and in vivo (34,44). Confirmatory evidences in our model came from reconstitution of Kit W-sh mice with BMMCs from mMCP-4 KO mice: mMCP-4 KO BMMCs were unable to promote mucosal healing after DSS withdrawal, unlike WT BMMCs.…”

Section: Discussionsupporting

confidence: 54%

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Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

et al. 2015

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Mast cells (MC) are immune cells located next to the intestinal epithelium with regulatory function in maintaining the homeostasis of the mucosal barrier. We have investigated MC activities in colon inflammation and cancer in mice either wildtype (WT) or MC-deficient (Kit W-sh ) reconstituted or not with bone marrow-derived MCs. Colitis was chemically induced with dextran sodium sulfate (DSS). Tumors were induced by administering azoxymethane (AOM) intraperitoneally before DSS. Following DSS withdrawal, Kit W-sh mice showed reduced weight gain and impaired tissue repair compared with their WT littermates or Kit W-sh mice reconstituted with bone marrowderived MCs. MCs were localized in areas of mucosal healing rather than damaged areas where they degraded IL33, an alarmin released by epithelial cells during tissue damage. Kit W-sh mice reconstituted with MC deficient for mouse mast cell protease 4 did not restore normal mucosal healing or reduce efficiently inflammation after DSS withdrawal. In contrast with MCs recruited during inflammation-associated wound healing, MCs adjacent to transformed epithelial cells acquired a protumorigenic profile. In AOM-and DSS-treated WT mice, high MC density correlated with high-grade carcinomas. In similarly treated Kit W-sh mice, tumors were less extended and displayed lower histologic grade. Our results indicate that the interaction of MCs with epithelial cells is dependent on the inflammatory stage, and on the activation of the tissue repair program. Selective targeting of MCs for prevention or treatment of inflammation-associated colon cancer should be timely pondered to allow tissue repair at premalignant stages or to reduce aggressiveness at the tumor stage. Cancer Res; 75(18); 3760-70. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 54%

“…5C), suggesting that IL33 is either sequestered or destroyed in the presence of MCs. The second hypothesis fits well with MCs known capacity to degrade HSP70, biglycan, HMGB1, and IL33 through the mouse homolog of the human chymase, mMCP-4 (34).…”

Section: Mast Cell Deficiency Impact On Epithelial Cells Activity Dursupporting

confidence: 52%

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

et al. 2015

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“…One possible candidate to carry out this function could be chymase, which was shown to be responsible for IL‐6 degradation mediated by human mast cells 12. On the other hand, studies on murine mast cells did not confirm this finding 36. Instead, it was shown that the tryptase mMCP6 (and not the chymase mMCP4) could cleave IL‐6, and that abrogation of this pathway in dipeptidyl peptidase I‐deficient mice could possibly explain their elevated levels of IL‐6 and improved survival in a model of septic peritonitis 13.…”

Section: Discussionmentioning

confidence: 98%

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Waern

Karlsson

Pejler³

et al. 2015

Immunity, Inflammation and Disease

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Mast cells contain large amounts of fully active proteases that are stored in complex with serglycin proteoglycan in their secretory granules. Upon degranulation, such serglycin:protease complexes are released to the extracellular space and can potentially have an impact on the local inflammatory reaction, either through direct effects of serglycin proteoglycan or through effects mediated by its bound proteases. The objective of this study was to address this scenario by investigating the possibility that serglycin‐associated proteases can regulate levels of pro‐inflammatory cytokines. Indeed, we show here that activated cultured peritoneal mast cells from wild type mice efficiently reduced the levels of exogenously administered IL‐6 and IL‐17A, whereas serglycin‐deficient mast cells lacked this ability. Furthermore, our data suggest that the reduction of IL‐6 and IL‐17A concentrations is due to proteolytic degradation mediated by serglycin‐dependent serine proteases. Moreover, we show that activated mast cells have the capacity to release IL‐6 and that the levels of this cytokine in supernatants were markedly higher in cultures of serglycin‐deficient versus serglycin‐sufficient mast cells, suggesting that serglycin‐dependent serine proteases also participate in the regulation of endogenously produced IL‐6. In summary, although the general consensus is that mast cells have a pathogenic impact on inflammatory settings, this study identifies a role for a mast cell‐derived serglycin:serine protease axis in down‐regulating levels of major inflammatory cytokines. These findings support the notion that mast cells could have a dual role in inflammatory settings, by both being able to secrete pathogenic compounds and being able to regulate their levels after release.

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“…is a recently finding cytokine with lots of functions. IL-33 has been reported as a potent inducer of Th2 immune responses as well as "alarmin" cytokine released from necrotic cells (Arshad et al, 2012;Lopetuso et al, 2012;Roy et al, 2014). Recently, some DOI:http://dx.doi.org/10.7314/APJCP.2014.15.8.3503 Correlations Between Serum IL33 and Tumor Development: a Meta-analysis researches reported that IL-33 is play important role in tumorigenesis and tumor progress (Chen et al, 2013;Jovanovic et al, 2014)Serum IL-33 may be a useful indicator for prognosis of tumor (Sun et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Correlations Between Serum IL33 and Tumor Development: a Meta-analysis

Chen

Huang²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Interleukin-33 (IL-33) has recently been implicated in tumor development. Methods: Data was obtained from PubMed, EMBASE, Clinical trial, Cochrane Library, Web of Science, CNKI and Wanfang databases. After quality assessment and data extraction, a meta-analysis was performed using Review Manager 5. 2 software. Results: There were eight documents included in this meta-analysis. The results showed IL33 levels to be higher in tumor patients than that in health people, but no correlations tumor stage, metastasis and survival time of tumor patients were evident. Conclusion: IL33 may be useful as an alarm factor in tumor detection and prognosis.

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Mast Cell Chymase Degrades the Alarmins Heat Shock Protein 70, Biglycan, HMGB1, and Interleukin-33 (IL-33) and Limits Danger-induced Inflammation

Cited by 110 publications

References 65 publications

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

Mast Cells Infiltrating Inflamed or Transformed Gut Alternatively Sustain Mucosal Healing or Tumor Growth

IL‐6 and IL‐17A degradation by mast cells is mediated by a serglycin:serine protease axis

Correlations Between Serum IL33 and Tumor Development: a Meta-analysis

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