Endotoxin Exposure during Sensitization to Blomia tropicalis Allergens Shifts TH2 Immunity Towards a TH17-Mediated Airway Neutrophilic Inflammation: Role of TLR4 and TLR2

Abstract

Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum-based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-γ axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-γdeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation.

TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract

“…Previous work of our group using the OVA‐model showed that the absorption of endotoxin LPS to alum adjuvant during the sensitization phase inhibited the development of Th2 responses, including IgE production . However, using B. tropicalis as allergen, the adsorption of endotoxin induced a neutrophilic lung inflammation . The activation of TLRs by endotoxin LPS in the OVA model dampened Th2 immunity without shifting toward Th1/Th17 immunity while in the B. tropicalis model it was observed a shift from Th2 toward a Th1/Th17 mediated lung inflammation .…”

“…However, using B. tropicalis as allergen, the adsorption of endotoxin induced a neutrophilic lung inflammation . The activation of TLRs by endotoxin LPS in the OVA model dampened Th2 immunity without shifting toward Th1/Th17 immunity while in the B. tropicalis model it was observed a shift from Th2 toward a Th1/Th17 mediated lung inflammation . More recently, we have shown that CpG‐ODN, a TLR9 agonist, during sensitization to OVA was the most effective TLR agonist in attenuating Th2‐mediated allergic responses.…”

“…However, a major criticism is the fact that OVA is a food allergen. Therefore, animal models have been adapted to airborne allergens derived from HDM …”

Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy

“…Further supporting a role of human FetA in patients with allergic inflammation, the latter was found to increase TLR4 activation by grass pollen or house dust mite extracts, which are known to contain both allergens and endotoxins. 29,30,50 Interestingly, this synergistic activation of the TLR4 pathway was largely diminished for neuraminidase-treated FetA, highlighting the key role of sialic acids branched on glycans in this proallergic cascade. In agreement with the recent identification of FetA as a central adaptor molecule contributing to fatty acid-mediated inflammation, our study confirms the capacity of FetA to interact with the TLR4 pathway and induce nuclear factor kB (NF-kB)-driven genes.…”

Safety of a proteoliposome fromNeisseria meningitidesas adjuvant for a house dust mite allergy vaccine

“…Such vaccination is believed to exert its beneficial effects on the immune system, at least in part, by modifying the T-helper (T H )-2 lymphocyte response to subsequent natural allergen exposure. The use of T H 1 promoting adjuvants in allergen-specific vaccines seems to be beneficial in allergic humans and animal models of allergic diseases (Pfaar et al 2012;Barboza et al 2013;Kun and Li 2016;Mohammadi-Shahrokhi et al 2017), and it is coherent with the anti-allergic effect of natural exposure to T H 1 microbial stimuli, promoting the so-called T H 1 deviation (Debarry et al 2007;Romagnani 2014). In addition, the use of immunopotentiating adjuvants has a potential to reduce the allergen content in the vaccine and ameliorate its safety.…”