Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells

Abstract

Prior exposure of dendritic cells (DCs) and monocytes/macrophages to LPS causes unresponsiveness to subsequent LPS stimulation, a phenomenon called endotoxin tolerance (ET). ET impairs antigen presentation of these cells to T cells by down-regulating expression of MHC class II and co-stimulatory molecules such as CD86 and CD40. Some epidemiological studies have shown that endotoxin acts as a protective factor for allergic diseases. Accordingly, LPS has beneficial effects on the onset of airway allergic inflammation in model animals by T(h)1 skewing or induction of regulatory T cells. However, results derived from asthma model animals are controversial, probably due to the difficulty of handling LPS. We previously generated a monoclonal agonistic antibody against Toll-like receptor (TLR) 4, named UT12, which mimics the biological activities of LPS, exhibiting more potent and sustained ET than does LPS. In this study, we took advantage of UT12 to generate prolonged ET to explore the possibility that ET is involved in the inhibitory effects of the TLR4 signals on asthma model mice. Induction of ET by UT12 inhibited the capacity of DCs to expand ovalbumin (OVA)-specific T(h)2 and T(h)17 cells, without inducing T(h)1 cell or regulatory T-cell populations or producing inhibitory cytokines. Accordingly, administration of UT12 before the OVA sensitization significantly suppressed airway allergic inflammation by OVA inhalation. Taken together, these results demonstrate that ET induced by activating TLR4 signals attenuates airway allergic inflammation through direct suppression of the T-cell stimulatory effect of DCs in asthma model mice.

Differential Uptake of Nanoparticles and Microparticles by Pulmonary APC Subsets Induces Discrete Immunological Imprints

“…It is tempting to speculate that the impaired Ag-specific costimulatory capacity of CD11b + DC we observed in the draining LN of PS50G-treated mice (11) is due to a state of PS50G-induced DC refractoriness, possibly occurring due to induction of DC maturation in the absence of specific Ag uptake. An analogous situation occurs during endotoxin tolerance in which refractory or exhausted DC are induced following LPS stimulation, resulting in suppression of AAI (57,58). Overall, these data increase our understanding of how differently sized inert nontoxic particles differentially modulate pulmonary APC function and lung immune homeostasis.…”

Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

“…Previous studies reported that the functions of several types of immune cells were modified via TLR4-dependent stimulation (30,(36)(37)(38). We were unable to ascertain whether the clinical efficacy of UT12 was due to its effect on neutrophils alone or resulted from its action on multiple immune response systems.…”

Endotoxemia Analysis by the Limulus Amoebocyte Lysate Assay in Different Mammal Species Used in Metabolic Studies

“…LBP and sCD14 can be considered as relevant markers of endotoxins in plasma [36]. In this respect, given the long half-lives of sCD14 and LBP (24-48 h) compared with endotoxin (from <8 min in mice to a maximum of 3 hours in humans), sCD14 and plasma LBP seem to reflect long-term exposure to endotoxin rather than the measurement of endotoxemia itself [37,38], which is more reliable to measure transient kinetics of endotoxin absorption [4,30]. We thus advise to measure others markers as LBP and sCD14 to complete endotoxemia [33,39,40].…”