title: Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Song
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Piliponsky
authors.forename: Martin
authors.initials: M
authors.lastname: Metz
authors.forename: Andrew
authors.initials: A
authors.lastname: Guzzetta
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrink
authors.forename: Susan M
authors.initials: SM
authors.lastname: Schlenner
authors.forename: Thorsten B
authors.initials: TB
authors.lastname: Feyerabend
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.forename: Gunnar
authors.initials: G
authors.lastname: Pejler
authors.forename: Mindy
authors.initials: M
authors.lastname: Tsai
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Galli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D043422:Carboxypeptidases A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D008116:Lizards; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000633:toxicity; D012604:Scorpion Venoms / Q000037:antagonists & inhibitors / Q000633:toxicity*; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000633:toxicity*; D014688:Venoms / Q000633:toxicity*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D012604:Scorpion Venoms; D014688:Venoms; D014660:Vasoactive Intestinal Peptide; C040442:heliodermin; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse; D012697:Serine Endopeptidases; C066932:mast cell protease 4