To our knowledge, this is the first study describing the differences in inflammasome activation in macrophages isolated from patients with Hymenoptera allergies and nonallergic individuals. These findings hold notable significance due to the limited knowledge surrounding innate immune responses in individuals with allergies and the potential role of innate immunity and inflammatory reactions in the development of type-I hypersensitivity.
Notably, allergic individuals displayed a substantial increase in pro-inflammatory signature and in the plasma concentrations of inflammasome-related cytokines, even during non-allergic periods, signifying the presence of a persistent systemic inflammatory signature. This observation aligns with recent hypotheses (Nakanishi, K., 2010; Kuroda-Morimoto, M., 2010; Kandikattu, H., 2019). The elevated plasma levels of IL-18 are consistent with recent studies that have demonstrated a connection between this inflammasome-derived cytokine and the Th2 immune response (Nakanishi, K., 2010; Kuroda-Morimoto, M., 2010; Kandikattu, H., 2019).
Macrophage from allergic donors displayed a heightened responsiveness to Hymenoptera venoms in terms of inflammasome activation, evident through increased IL-1ß release and pyroptosis. The rapid and robust pro-inflammatory effects induced by the venoms, through the inflammasome, could potentially serve as the initial trigger for the development of type-1 hypersensitivity.
Despite the limitations of our in vitro model, these findings contribute to a deeper understanding of previous genetic studies that have linked NLRP3 inflammasome-related genes with type-1 hypersensitivity, including conditions such as aspirin and food allergies, as well as asthma (Hitomi et al., 2009; Bruchard et. al., 2015, Queiroz et al., 2020).
A previous study in an animal model of allergic rhinitis has shown that the NLRP3 or caspase-1 deficiency ameliorates the disease progression without serum IgE alteration, reducing the local Th2 inflammation through a still not elucidated mechanism (Yang et al., 2020). These results strongly support the role of NLRP3 inflammasome in allergic disease (Xiao et al, 2018), and indicate that specific NLRP3 inflammasome inhibitors may be potential therapeutic agents for allergic diseases.
Our findings have demonstrated that venoms from various Hymenoptera insects, including wasps and ants, and not just honey bees (Martín-Sánchez, F., 2017; Dombrowski, Y., 2012), possess the ability to activate the inflammasome, suggesting a common innate immune response against insect sting. However, the precise mechanism underlying the activation of the inflammasome by these venoms warrants further investigation.
It is interesting to note that honey bee venom contains at least two compounds known to trigger NLRP3 activation: melittin and phospholipase A2 (PLA2) (Palm, N.W., and Medzhitov, R., 2013). The toxin peptide melittin is known to induce canonical NLRP3 inflammasome activation by plasma membrane permeabilization and K+ efflux, which results in caspase-1 activation and IL-1ß release, but not pyroptosis ((Martín-Sánchez, F., 2017). K+ efflux also leads to the activation of PLA2, which promotes IL-1β maturation (Walev et. al., 2000).
Wasp venom lacks melittin but contains PLA2 and other components, such as hyaluronidases (Fitzgerald, K.T., Flood, A.A., 2006), which may play a role in NLRP3 inflammasome activation (Próchnicki & Latz, 2017).
In contrast to bee and wasp venoms, which consist mainly of protein-based cytotoxic components, ant venom is predominantly made up of water-insoluble alkaloids which have cytotoxic and hemolytic properties (Fitzgerald, K.T., Flood, A.A., 2006). The aqueous phase of ant venom contains the major allergens and also hyaluronidases and phospholipases (Palm, N.W., and Medzhitov, R., 2013; Fitzgerald, K.T., Flood, A.A., 2006). Therefore, the membrane damage induced by either alkaloids, hyaluronidase, or phospholipases, can result in the activation of NLRP3 inflammasome.
Despite having different compositions, Hymenoptera venoms are capable of activating the inflammasome. Thus, it is possible to infer that the inflammasome is an important immune tool in combating Hymenoptera venoms.