Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice
Mitsuteru Akahoshi, … , Mindy Tsai, Stephen J. Galli
Mitsuteru Akahoshi, … , Mindy Tsai, Stephen J. Galli
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):4180-4191. https://doi.org/10.1172/JCI46139.
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Research Article Immunology

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

Mitsuteru Akahoshi, Chang Ho Song, Adrian M. Piliponsky, Martin Metz, Andrew Guzzetta, Magnus Åbrink, Susan M. Schlenner, Thorsten B. Feyerabend, Hans-Reimer Rodewald, Gunnar Pejler, Mindy Tsai, Stephen J. Galli

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Figure 2

Mast cells and MCPT4 can diminish helodermin-induced hypothermia and diarrhea in mice.

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Mast cells and MCPT4 can diminish helodermin-induced hypothermia and dia...
Changes in rectal temperatures after i.d. injection of helodermin (5 nmol in 20 μl DMEM solution) in ear pinnae (1 ear pinna of each mouse). (A) WT C57BL/6-Kit+/+, C57BL/6-KitW-sh/W-sh, WT BMCMC→KitW-sh/W-sh, and Mcpt4–/– BMCMC→KitW-sh/W-sh mice. The rates of diarrhea within 2 hours after helodermin injection in Kit+/+, WT BMCMC→KitW-sh/W-sh, Mcpt4–/– BMCMC→KitW-sh/W-sh, and KitW-sh/W-sh mice were 20% (2/10), 50% (4/8, P = 0.2 versus Kit+/+ mice), 100% (5/5, P = 0.007 versus Kit+/+ mice), and 100% (11/11, P = 0.0002 versus Kit+/+ mice), respectively. (B) C57BL/6 WT, Cpa3Y356L,E378A, and Mcpt4–/– mice. The rates of diarrhea within 2 hours after helodermin injection in Kit+/+, Cpa3Y356L,E378A, and Mcpt4–/– mice were 22% (2/9), 50% (4/8, P = 0.25 versus Kit+/+ mice), and 100% (9/9, P = 0.001 versus Kit+/+ mice), respectively. *P < 0.05; ***P < 0.001 versus WT Kit+/+ mice; †P < 0.05~0.001 versus each of the other groups (A and B). Each panel shows data pooled from at least 3 independent experiments with each group of mice except for Mcpt4–/– BMCMC→KitW-sh/W-sh mice, with which 2 independent experiments were performed (n = 1–3 mice per group per experiment). Data are presented as mean ± SEM.