Toll-Like Receptor Ligands LPS and Poly (I:C) Exacerbate Airway Hyperresponsiveness in a Model of Airway Allergy in Mice, Independently of Inflammation

Abstract

It is well-established that bacterial and viral infections have an exacerbating effect on allergic asthma, particularly aggravating respiratory symptoms, such as airway hyperresponsiveness (AHR). The mechanism by which these infections alter AHR is unclear, but some studies suggest that Toll-like receptors (TLRs) play a role. In this study, we investigated the impact of TLR3 and TLR4 ligands on AHR and airway inflammation in a model of pre-established allergic inflammation. Female BALB/c mice were sensitised and challenged intranasally (i.n.) with either PBS or ovalbumin (OVA) and subsequently i.n. challenged with poly (I:C) (TLR3) or LPS (TLR4) for four consecutive days. The response to methacholine was measured in vivo; cellular and inflammatory mediators were measured in blood, lung tissue and broncheoalveolar lavage fluid (BALF). OVA challenge resulted in an increase in AHR to methacholine, as well as increased airway eosinophilia and TH2 cytokine production. Subsequent challenge with TLR agonists resulted in a significant increase in AHR, but decreased TLR-specific cellular inflammation and production of immune mediators. Particularly evident was a decline in LPS-induced neutrophilia and neutrophil-associated cytokines following LPS and poly (I:C) treatment. The present data indicates that TLRs may play a pivotal role in AHR in response to microbial infection in allergic lung inflammation. These data also demonstrate that aggravated AHR occurs in the absence of an exacerbation in airway inflammation and that allergic inflammation impedes a subsequent inflammatory response to TLRs. These results may parallel clinical signs of microbial asthma exacerbation, including an extended duration of illness and increased respiratory symptoms.

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

“…Moreover, poly(I:C) was also able to enhance HDMinduced AHR. These data are consistent with recent data, using force oscillations, where poly(I:C) exacerbated OVA-induced AHR [22]. The up-regulation of IL-17A and IL-33 associated with our model could co-operate to exacerbate AHR by enhancing neutrophilic inflammation [23].…”

TNF-α and Macrophages Are Critical for Respiratory Syncytial Virus–Induced Exacerbations in a Mouse Model of Allergic Airways Disease

“…We propose that acute inflammation acts together with underlying Th2 inflammation to exacerbate AHR. Similarly, although LPS administration can stimulate neutrophilia and increase inflammatory mediators (such as TNF-a, IL-1, and IL-6), LPS stimulation alone does not induce AHR unless there is a pre-existing Th2 background (34,58,59). Collectively, these findings indicate that RSVinduced exacerbation of AHR and airway inflammation are not driven by increased Th2 responses and eosinophil infiltration, but rather may be induced by increased expression of TNF-a and MCP-1 and innate immune cell activation, in particular macrophages.…”

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells

“…TargetScan analysis predicts that miR-26a targets Toll-like receptor 3 (TLR3). TLR3 plays a pivotal role in airway hyperresponsiveness in response to microbial infection in allergic lung inflammation (36). In mice with allergic airway inflammation, dsRNA (a ligand of TLR3) challenge causes a significant exacerbation, increasing lung tissue inflammation score and tissue neutrophilia (37).…”