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.

Imaging protective mast cells in living mice during severe contact hypersensitivity

“…We therefore investigated whether incorporation of fluorochrome-labeled avidin could interfere with MC degranulation, the release of granule-associated mediators, or the induction of classical MC-dependent allergic inflammation at sites of IgE-dependent passive cutaneous anaphylaxis (PCA). We incubated in vitro bone marrow-derived cultured MCs (BMCMCs) with Av.SRho for 4 days (the time required to observe substantial incorporation of Av.SRho into their secretory granules [Supplemental Figure 1C]) and measured the quantity of β-hexosaminidase release (27) in their supernatants upon IgE/Ag challenge. While we barely detected the presence of β-hexosaminidase in supernatants of nonstimulated control BMCMCs, we measured comparable quantities of the enzyme in the supernatants of Av.SRho -or Av.SRho + BMCMCs stimulated with IgE/Ag (Supplemental Figure 1D).…”

Role of the inflammasome in defense against venoms

“…Mast cell proteases released during degranulation can detoxify venom components via direct cleavage and inactivation of venom toxins (22,25). Furthermore, heparin, which is one of the major components of mast cell granules, can detoxify bee venom by binding and neutralizing cationic venom toxins (26,27).…”

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

“…Notably, human tryptase can favour the recruitment of inflammatory cells by activating endothelial cells via protease-activated receptors such as PAR-2 (refs [15][16][17]. Moreover, in vivo studies provided evidence of direct or indirect protective roles of mast cell chymase against infection 18 or vasoactive agents 19,20 .…”