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BackgroundGroup 2 innate lymphoid cells (ILC2s) expand in the lungs of mice during type 2 inflammation induced by the fungal allergen Alternaria alternata. The increase in ILC2 numbers in the lung has been largely attributed to local proliferation and whether ILC2s migrate from the circulation to the lung after Alternaria exposure is unknown.ObjectiveWe examined whether human (lung, lymph node, and blood) and mouse lung ILC2s express β1 and β2 integrin adhesion molecules and whether these integrins are required for trafficking of ILC2s into the lungs of mice.MethodsHuman and mouse ILC2s were assessed for surface expression of β1 and β2 integrin adhesion molecules by using flow cytometry. The role of β1 and β2 integrins in ILC2 trafficking to the lungs was assessed by in vivo blocking of these integrins before airway exposure to Alternaria in mice.ResultsBoth human and mouse lung ILC2s express high levels of β1 and β2 integrin adhesion receptors. Intranasal administration of Alternaria challenge reduced ILC2 numbers in the bone marrow and concurrently increased blood and lung ILC2 numbers. In vivo blocking of β2 integrins (CD18) significantly reduced ILC2 numbers in the lungs but did not alter ILC2 proliferation, apoptosis, and function. In contrast, in vivo blocking of β1 integrins or α4 integrins did not affect lung ILC2 numbers.ConclusionILC2 numbers increase in the mouse lung not only through local proliferation but also through trafficking from the circulation into the lung using β2 rather than β1 or α4 integrins.

Orosomucoid like 3 (ORMDL3), a gene localized to chromosome 17q21, has been linked in epidemiologic studies to childhood asthma and rhinovirus (RV) infections. As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3zp3-Cre mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load. RV infection of hORMDL3zp3-Cre mice resulted in reduced RV viral load assessed by quantitative real-time PCR (lung and airway epithelium), as well as reduced airway inflammation (total bronchoalveolar lavage cells, neutrophils, macrophages, and lymphocytes) compared with RV-infected wild-type mice. Levels of the antiviral pathways including IFNs (IFN-α, IFN-β, IFN-λ) and RNAse L were significantly increased in the lungs of RV-infected hORMDL3zp3-Cre mice. Levels of the antiviral mouse oligoadenylate synthetase (mOas)1g pathway and RNAse L were upregulated in the lungs of unchallenged hORMDL3zp3-Cre mice. In addition, levels of mOas2, but not mOas1 (mOas1a, mOas1b, mOas1g), or mOas3 pathways were significantly more upregulated by IFNs (IFN-α, IFN-β, IFN-λ) in epithelial cells from hORMDL3zp3-Cre mice compared with RV-infected wild-type mouse epithelial cells. RNAse L-deficient mice infected with RV had increased RV viral load. Overall, these studies suggest that increased levels of ORMDL3 contribute to antiviral defense to RV infection in mice through pathways that may include IFNs (IFN-α, IFN-β, IFN-λ), OAS, and RNAse L.

In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challenged Ormdl3Δ2-3/Δ2-3/CC10 mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in Ormdl3Δ2-3/Δ2-3/CC10 and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3/CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3/CC10 mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.

Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-β1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMBZp3-Cre mice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMBZp3-Cre mice showed increases in the same remodeling and AHR mediators (TGF-β1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-β1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells overexpressing GSDMB inhibited TGF-β1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-β1 in bronchial epithelium.

Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/Δ) mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma.

Allometric relationships among the dimensions of leaves and their cells hold across diverse eudicotyledons, but have remained untested in the leaves of grasses. We hypothesised that geometric (proportional) allometries of cell sizes across tissues and of leaf dimensions would arise due to the coordination of cell development and that of cell functions such as water, nutrient and energy transport, and that cell sizes across tissues would be associated with light‐saturated photosynthetic rate. We tested predictions across 27 globally distributed C3 and C4 grass species grown in a common garden. We found positive relationships among average cell sizes within and across tissues, and of cell sizes with leaf dimensions. Grass leaf anatomical allometries were similar to those of eudicots, with exceptions consistent with the fewer cell layers and narrower form of grass leaves, and the specialised roles of epidermis and bundle sheath in storage and leaf movement. Across species, mean cell sizes in each tissue were associated with light‐saturated photosynthetic rate per leaf mass, supporting the functional coordination of cell sizes. These findings highlight the generality of evolutionary allometries within the grass lineage and their interlinkage with coordinated development and function. Summary statement: Allometries among leaf cell sizes and of cell sizes with leaf dimensions and photosynthetic rate hold across grass species, supporting their basis in developmental and functional coordination. [ABSTRACT FROM AUTHOR]

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Background: Group 2 innate lymphoid cells (ILC2s) expand in the lungs of mice during type 2 inflammation induced by the fungal allergen Alternaria alternata. The increase in ILC2 numbers in the lung has been largely attributed to local proliferation and whether ILC2s migrate from the circulation to the lung after Alternaria exposure is unknown. Objective: We examined whether human (lung, lymph node, and blood) and mouse lung ILC2s express β1 and β2 integrin adhesion molecules and whether these integrins are required for trafficking of ILC2s into the lungs of mice. Methods: Human and mouse ILC2s were assessed for surface expression of β1 and β2 integrin adhesion molecules by using flow cytometry. The role of β1 and β2 integrins in ILC2 trafficking to the lungs was assessed by in vivo blocking of these integrins before airway exposure to Alternaria in mice. Results: Both human and mouse lung ILC2s express high levels of β1 and β2 integrin adhesion receptors. Intranasal administration of Alternaria challenge reduced ILC2 numbers in the bone marrow and concurrently increased blood and lung ILC2 numbers. In vivo blocking of β2 integrins (CD18) significantly reduced ILC2 numbers in the lungs but did not alter ILC2 proliferation, apoptosis, and function. In contrast, in vivo blocking of β1 integrins or α4 integrins did not affect lung ILC2 numbers. Conclusion: ILC2 numbers increase in the mouse lung not only through local proliferation but also through trafficking from the circulation into the lung using β2 rather than β1 or α4 integrins. [ABSTRACT FROM AUTHOR]

Antibiotic growth promoters (AGP) are well documented to play an important role in the feed efficiency of poultry. However, recent regulations and consumer demand are globally decreasing their use, resulting in a surge of research focused on the search for replacement compounds and probiotics in order to maintain current levels of performance in poultry. However, unless the mechanisms by which AGP modulate growth and feed conversion in animals are well understood, scientists and producers will struggle to find successful alternatives. This review discusses possible mechanisms of action of AGP on the host, rather than direct anti-microbial effects on gastrointestinal microflora, and the possible roll that probiotics may play decreasing gastrointestinal inflammatory responses. For example, some probiotics may be able to decrease colonization by pathogens that exploit inflammation to enhance colonization by decreasing innate inflammatory responses, including macrophage activation phenotypes. Probiotics are also well documented to increase modulation of adaptive immunity. These findings suggest nuanced strain-specific immune interactions in regards to probiotic cultures and the need for proper characterization of each microbial strain for its abilities to enhance protection against pathogenic insult and maintain health and homeostasis via immunomodulation of the enteric and systemic environments to enhance growth performance and health. [ABSTRACT FROM AUTHOR]

Orosomucoid like 3 (ORMDL3), a gene localized to chromosome 17q21, has been linked in epidemiologic studies to childhood asthma and rhinovirus (RV) infections. As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3zp3-Cre mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load. RV infection of hORMDL3zp3-Cre mice resulted in reduced RV viral load assessed by quantitative real-time PCR (lung and airway epithelium), as well as reduced airway inflammation (total bronchoalveolar lavage cells, neutrophils, macrophages, and lymphocytes) compared with RV-infected wild-type mice. Levels of the antiviral pathways including IFNs (IFN-α, IFN-ß, IFN-l) and RNAse L were significantly increased in the lungs of RV-infected hORMDL3zp3-Cre mice. Levels of the antiviral mouse oligoadenylate synthetase (mOas)1g pathway and RNAse L were upregulated in the lungs of unchallenged hORMDL3zp3-Cre mice. In addition, levels of mOas2, but not mOas1 (mOas1a, mOas1b, mOas1g), or mOas3 pathways were significantly more upregulated by IFNs (IFN-a, IFN-ß, IFN-l) in epithelial cells from hORMDL3zp3-Cre mice compared with RV-infected wild-type mouse epithelial cells. RNAse L-deficient mice infected with RV had increased RV viral load. Overall, these studies suggest that increased levels of ORMDL3 contribute to antiviral defense to RV infection in mice through pathways that may include IFNs (IFN-α, IFN-ß, IFN-l), OAS, and RNAse L. [ABSTRACT FROM AUTHOR]