The effect of IRE1 pharmacological modulators on respiratory allergen-specific antibody production

One of the leading hypotheses explaining the increase in the incidence of IgE-dependent pathologies in the population of developed countries is the hypothesis about the leading role of air pollutants, including polycyclic aromatic hydrocarbons (PAHs). PAHs such as benzo(a)pyrene (BaP) are known to activate molecular mechanisms associated with ER stress in damaged cells, including the endonuclease IRE1. The aim of this work was to analyze the effect of modulators of this enzyme on the humoral response when a respiratory allergen enters the body together with BaP. The study used BALB/c mice, immunized intranasally with the allergen ovalbumin (OVA) for 10 weeks in the presence of BaP. Small-molecule pharmacological inhibitors of IRE1 at doses of 3 mg/kg were administered to experimental groups. We used 4µ8C and APY-29 as IRE1 inhibitors. Antibody production was analyzed using ELISA in serum samples, recording their titer. Administration of BaP significantly increased the production of allergen-specific IgE (p>0.001), IgG1 (p<0.01), IgA (p<0.01), and IgG2b (p<0.05), while simultaneously suppressing the production of IgG2a (p<0.01). At the doses used, when administered intranasally together with the allergen, the pharmacological modulator 4µ8C significantly (p<0.05) and noticeably (approximately 5 times) reduced the production of OVA-specific IgE, but the suppression of IgG1 production was even more reliable and noticeable (p<0.01, 8 times in absolute terms). In both cases, however, blocking the production of allergen-specific antibodies was incomplete (in the corresponding groups, a significant difference with the negative control group remained). 4µ8C had no significant effect on the production of allergen-specific IgG2a. The pharmacological modulator APY-29 had no significant effect on the production of specific IgE, while significantly (by more than an order of magnitude in absolute terms, p<0.001) suppressing the production of allergen-specific IgG1 antibodies. At the same time, in the presence of APY-29, significantly higher production of IgG2a was observed in the experimental groups (an order of magnitude higher in absolute values, p<0.01). Thus, IRE1 modulators, especially 4µ8C, may be promising for use in the prevention of early stages of allergic pathologies, when it is most important to suppress the formation of an anaphylactogenic IgE-dependent immune response.

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