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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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 1

Mast cells can diminish H. suspectum venom–induced (H.s. venom–induced) hypothermia and mortality through MCPT4-dependent mechanisms.

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Mast cells can diminish H. suspectum venom–induced (H.s. venom–induced) ...
Changes in rectal temperatures after i.d. injection of H. suspectum venom (25 μg in 20 μl DMEM solution) into ear pinnae (1 ear pinna of each mouse). (A) WT WBB6F1-Kit+/+, mast cell–deficient WBB6F1-KitW/W-v, and WT BMCMC→KitW/W-v mice. Death rates of Kit+/+, WT BMCMC→KitW/W-v, and KitW/W-v mice within 24 hours after H. suspectum venom injection were 0% (0/21), 7% (1/15; P = 0.42 versus Kit+/+ mice), and 65% (13/20; P < 0.0001 versus Kit+/+ mice), respectively. (B) WT C57BL/6-Kit+/+, mast cell–deficient C57BL/6-KitW-sh/W-sh, WT BMCMC→KitW-sh/W-sh, and Mcpt4–/– BMCMC→KitW-sh/W-sh mice. Death rates of Kit+/+, WT BMCMC→KitW-sh/W-sh, Mcpt4–/– BMCMC→KitW-sh/W-sh, and KitW-sh/W-sh mice within 24 hours after H. suspectum venom injection were 5% (1/19), 11% (2/18, P = 0.48 versus Kit+/+ mice), 43% (6/14; P = 0.01 versus Kit+/+ mice), and 50% (10/20; P = 0.006 versus Kit+/+ mice), respectively. (C) WT C57BL/6-Kit+/+, C57BL/6-Cpa3Y356L,E378A, and C57BL/6-Mcpt4–/– mice. Death rates of Kit+/+, Cpa3Y356L,E378A, and Mcpt4–/– mice within 24 hours after H. suspectum venom injection were 7% (1/15), 0% (0/14; P = 0.52 versus Kit+/+ mice), and 40% (6/15, P = 0.007 versus Kit+/+ mice), respectively. Each panel shows data pooled from at least 3 independent experiments with each group of mice (n = 2–5 mice per group per experiment). **P < 0.01; ***P < 0.001 versus WT WBB6F1-Kit+/+ or WT C57BL/6-Kit+/+ mice; †P < 0.01~0.001 versus each of the other groups (A–C). (D) Extensive degranulation of mast cells (some indicated by black arrowheads) 1 hour after i.d. injection of H. suspectum venom (25 μg in 20 μl DMEM), but not vehicle (DMEM) alone (mast cells without evidence of degranulation are indicated by white arrowheads) in WT C57BL/6 mice (toluidine blue stain). Scale bar: 50 μm. (E) Degranulation of mast cells 60 minutes after i.d. injection of H. suspectum venom (25 μg in 20 μl DMEM) or vehicle (DMEM) alone in WT C57BL/6, Mcpt4–/–, or Cpa3Y356L,E378A mice (injection was into 1 ear pinna of each mouse). ***P < 0.001 versus corresponding vehicle-injected groups; NS (P > 0.05) versus values for WT mice. Data are presented as mean ± SEM (A–C) or mean + SEM (E).