A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death.

Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.

Mammalian airborne allergens.

Historically, horse dandruff was a favorite allergen source material. Today, however, allergic symptoms due to airborne mammalian allergens are mostly a result of indoor exposure, be it at home, at work or even at school. The relevance of mammalian allergens in relation to the allergenic activity of house dust extract is briefly discussed in the historical context of two other proposed sources of house dust allergenic activity: mites and Maillard-type lysine-sugar conjugates. Mammalian proteins involved in allergic reactions to airborne dust are largely found in only 2 protein families: lipocalins and secretoglobins (Fel d 1-like proteins), with a relatively minor contribution of serum albumins, cystatins and latherins. Both the lipocalin and the secretoglobin family are very complex. In some instances this results in a blurred separation between important and less important allergenic family members. The past 50 years have provided us with much detailed information on the genomic organization and protein structure of many of these allergens. However, the complex family relations, combined with the wide range of post-translational enzymatic and non-enzymatic modifications, make a proper qualitative and quantitative description of the important mammalian indoor airborne allergens still a significant proteomic challenge.

IgE antibodies to animal-derived lipocalin, kallikrein and secretoglobin are markers of bronchial inflammation in severe childhood asthma.

BACKGROUND: Component-resolved allergy diagnostics enables the detection of crossreactive or species-specific allergen components. This study analysed Immunoglobulin E (IgE) profiles to single allergen components in relation to bronchial inflammation in severe childhood asthma. METHODS: Ninety-five schoolchildren were assessed, 39 with controlled mild-to-moderate asthma and 56 uncontrolled severe asthmatics. Allergen components (n = 111) of food allergens, pollen and perennial aeroallergens were analysed using an immunosolid-phase allergen chip. Blood eosinophils (10(9) × l(-1)), bronchial inflammation (FeNO, ppb), lung function (FEV(1)%) and bronchial hyper-responsiveness (BHR) (dose-response slope of methacholine challenge) were measured. RESULTS: A specific IgE response to more than three animal-derived components--lipocalin (nMus m 1, rEqu c 1, Fel d 4, rCan f 1, 2), kallikrein (rCan f 5) and secretoglobin (rFel d 1)--was more common among severe asthmatics compared to children with controlled asthma (n = 14 vs n = 3, P = 0.030). These subjects also displayed higher blood eosinophils (0.65 vs 0.39, P = 0.021), higher Fractional exhaled nitric oxide (38 ppb vs 25 ppb, P = 0.021) and increased BHR (112 vs 28, P = 0.002) compared to other severe asthmatics positive to fewer lipocalin/kallikrein/secretoglobin components. Among all sensitized subjects, there were correlations between specific IgE levels for rFel d 4 and nMus m 1 (r = 0.751, P ≤ 0.001) and for rFel d 4 and rEqu c 1 (r = 0.850, P ≤ 0.001). CONCLUSION: Multi-sensitization towards lipocalin, kallikrein and secretoglobin components is associated with increased bronchial inflammation in severe asthmatics. In addition, crossreactive patterns were observed between different lipocalin components.

Uteroglobulin-related protein 1 and severity of respiratory syncytial virus infection in children admitted to hospital.

There are several reports suggesting that genetic factors contribute to the severity of infection with the respiratory syncytial virus (RSV). Infants hospitalized with lower respiratory tract infection (LRTI) due to RSV are at a significantly increased risk for both recurrent wheezing and childhood asthma. Uteroglobin-related protein 1 (UGRP1) is a secretory protein expressed in the airways, and speculated to have anti-inflammatory activity. The presence of the -112G/A polymorphism in the UGRP1 promoter was found to have a significant correlation with asthma phenotype. Also plasma UGRP1 levels were shown to be associated both with this polymorphism and the severity of asthma. The study population consisted of 62 previously healthy infants, ≤12 months of age, who were hospitalized with RSV LRTI, and a control group of 99 healthy adults. Genotyping was performed by restriction fragment length polymorphism. UGRP1 serum levels were determined using ELISA. There were no significant differences in the overall distribution of UGRP1 -112G/A polymorphism genotypes or alleles between the hospitalized infants and healthy adults. A comparison of serum UGRP1 concentration measured at the time of admission and discharge between patients with and without the -112A allele revealed that there was no relation between the presence of the -112A allele and serum UGRP1 in hospitalized infants with RSV infection. Furthermore, there was no relationship between severity of RSV infection and genotype or serum UGRP1 concentration. These results suggest that UGRP1 does not have a major role in the development of severe RSV infection.