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 6

Mast cell chymase can degrade either VIP or helodermin.

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Mast cell chymase can degrade either VIP or helodermin. (A) VIP (125 μM ...
(A) VIP (125 μM in 150 μl) or (B) helodermin (125 μM in 150 μl) was incubated ex vivo at 37°C for 30 minutes with medium (DMEM) alone (no mast cells) or with medium containing purified PMCs (8 × 105) from WT C57BL/6 mice (WT PMCs), C57BL/6-Mcpt4–/– mice (Mcpt4–/– PMCs), or C57BL/6-Cpa3Y356L,E378A mice (Cpa3Y356L,E378A PMCs); supernatants were then analyzed by mass spectrometry. Red arrows indicate cleavage sites found in (A) VIP or (B) helodermin after incubation with WT PMCs but not Mcpt4–/– PMCs. The long blue arrow indicates the single cleavage site in VIP that was found after incubation with either WT or Mcpt4–/– PMCs. White arrows indicate sites predicted to be susceptible to cleavage, and the dashed arrow indicates a previously reported cleavage site. The figure depicts results obtained in 2 independent experiments that gave similar results.