LIPOPOLYSACCHARIDE-ENHANCED, TOLL-LIKE RECEPTOR 4-DEPENDENT, T HELPER CELL TYPE 2 RESPONSES TO INHALED ANTIGEN

Abstract

Eisenbarth SC, Piggott DA, Huleatt JW, et al. J Exp Med. 2002;196:1645–1651To evaluate the dose-dependent effects of lipopolysaccharide (LPS) (endotoxin) inhalation and LPS-induced activation of toll-like receptor 4 (TLR4) on the generation of T helper (Th) cell type 2-dependent allergic inflammatory responses to an inhaled antigen, ovalbumin (OVA).Wild-type or TLR4-deficient, 6- to 10-week-old, female mice were studied.Mice were sensitized with intranasal exposure to LPS-depleted OVA or OVA with either a low (0.1 μg) or high (100 μg) dose of LPS. After intranasal OVA challenge, pulmonary inflammatory responses were assessed through enumerating bronchoalveolar lavage cells, performing histopathologic analyses, measuring OVA-dependent cytokine production by lung-draining lymph node cells, and determining OVA-specific serum antibody levels. Dendritic cell responses to OVA with LPS were evaluated in cytokine production, activation marker expression, and cell migration studies.After antigen challenge, mice sensitized to OVA with low-dose LPS exhibited a Th2-associated response, with pulmonary eosinophilia, airway mucus secretion, Th2 cytokine (interleukin-5 and -13) production by lymph node cells, and production of high levels of OVA-specific immunoglobulin E and immunoglobulin G1. In contrast, mice sensitized to OVA with high-dose LPS developed a Th1-associated response, with a predominance of neutrophils, no airway mucus secretion, Th1 cytokine (interferon-γ) production by lymph node cells, and production of high levels of OVA-specific immunoglobulin G2a. No pulmonary inflammatory responses were observed with mice sensitized to LPS-depleted OVA. OVA sensitization of TLR4-deficient mice with either low- or high-dose LPS failed to generate inflammatory responses. However, treatment with tumor necrosis factor, which is secreted by LPS-stimulated dendritic cells, compensated for deficient dendritic cell activation, restoring the responses of TLR4-deficient mice to OVA with either low- or high-dose LPS.The authors concluded that inhalation of low doses of LPS with OVA antigen was necessary to induce allergic or Th2-dependent responses in the lung, whereas inhalation of high doses of LPS with antigen induced nonallergic or Th1-dependent responses. The LPS-mediated effects on allergic sensitization were dependent on signaling through TLR4 on dendritic cells.The effects of endotoxin exposure on the development of atopy and asthma are seemingly paradoxical. Although studies show that exposure to endotoxin early in life inhibits the development of asthma and atopic disease, other studies demonstrate adverse effects of endotoxin on airway function. Although endotoxin is ubiquitous in children’s environments, the exposure level can vary and may be the factor influencing the development of atopy. For example, this dosage effect may help explain the protection from atopy associated with growing up on a farm, where endotoxin exposure is excessive. The results of this study are an intriguing advance toward understanding the basis for these conflicting data, suggesting a mechanism through which the dose of endotoxin present during aeroallergen exposure could influence the incidence of allergic sensitization.