Allergic asthma is thought to stem from inappropriate immune responses to inhaled antigens. Therefore, to prevent or treat allergic asthma, it is important to identify the cellular and molecular mechanisms that initially give rise to allergic sensitization, as well as the pathways that regulate allergic inflammation once it has begun. Accordingly, our laboratory uses a mouse model of asthma in which the animals are senstized to inhaled allergens. Ovalbumin (OVA) is delivered to the airway together with various adjuvants. Such adjuvants include ligands of various toll-like receptors (TLRs), including lipopolysaccharide (LPS) and bacterial flagellin. Pulmonary dendritic cells lining the airway epithelium take up OVA and migrate to draining thoracic lymph nodes to present OVA-derived peptides to nave T cells. We have found that this method of sensitization primes a qualitatively different type of immune response than the more conventional method of sensitization involving intraperitoneal (i.p.) injections of OVA complexed with aluminum hydroxide (alum). Thus, sensitization through the airway, but not through the peritoneum, induces robust T helper (Th)17 responses. These Th17 cells produce IL-17 upon challenge with OVA that in turn leads to airway neutrophilia and airway hyperresponsiveness (AHR). Ongoing Th17 responses to inhaled allergens might therefore distinguish severe asthma from less serious Th2-mediated diseases of the airway. In addition to studying the mechanisms underlying the induction and actions of Th2 and Th17 cells in the lung, we also study the impact of various environmental agents on pulmonary dendritic cell activation, and how these agents can act as adjuvants in the lung to promote allergic sensitization through the airway. For example, we have found that the bacterial product, flagellin, primes very strong allergic responses to the experimental allergen, OVA, as well as to natural allergens present in common house dust. Efforts to understand the mechanism by which flagelling promotes allergic sensitization are currently underway. There are two major subsets of resident lung dendritic cells. One subset displays the cell surface molecule, CD103, whereas the other subset displays a different marker, CD11b. The latter can be divided into three distinct subsets by flow cytometery. We are comparing the functions of these four dendritic cell subsets following their enrichment by flow cytometry-based sorting and culture with antigen-specific T cells. The cellular origin of dendritic cell subsets remains unclear. Although the chemokine receptors, CCR2 and CX3CR1 have both been implicated in the recruitment of monocytes to the lung, it is not known whether monocytes displaying these two molecules give rise to pulmonary dendritic cells having different functional properties. One of the projects in our laboratory is directed at identifying such differences, including the T cell activating functions and migratory properties of these different dendritic cell lineages. Together, these approaches should allow us to identify and characterize cellular and molecular mechanisms that lead to allergic sensitization to inhaled allergens.
| Immormino, Robert M; Lauzier, David C; Nakano, Hideki et al. (2018) Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol 315:L202-L211 |
| Thomas, S Y; Whitehead, G S; Takaku, M et al. (2018) MyD88-dependent dendritic and epithelial cell crosstalk orchestrates immune responses to allergens. Mucosal Immunol 11:796-810 |
| Lyons-Cohen, Miranda R; Nakano, Hideki; Thomas, Seddon Y et al. (2018) Imaging Precision-Cut Lung Slices to Visualize Leukocyte Localization and Trafficking. Methods Mol Biol 1799:237-246 |
| Shalaby, Karim H; Lyons-Cohen, Miranda R; Whitehead, Gregory S et al. (2018) Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling. J Allergy Clin Immunol 142:1229-1242.e6 |
| Burns, Katherine A; Thomas, Seddon Y; Hamilton, Katherine J et al. (2018) Early Endometriosis in Females Is Directed by Immune-Mediated Estrogen Receptor ? and IL-6 Cross-Talk. Endocrinology 159:103-118 |
| Nakano, Hideki; Nakano, Keiko; Cook, Donald N (2018) Isolation and Purification of Epithelial and Endothelial Cells from Mouse Lung. Methods Mol Biol 1799:59-69 |
| Zhang, Song; Takaku, Motoki; Zou, Liyun et al. (2017) Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551:105-109 |
| Nakano, Hideki; Lyons-Cohen, Miranda R; Whitehead, Gregory S et al. (2017) Distinct functions of CXCR4, CCR2, and CX3CR1 direct dendritic cell precursors from the bone marrow to the lung. J Leukoc Biol 101:1143-1153 |
| Whitehead, Gregory S; Thomas, Seddon Y; Shalaby, Karim H et al. (2017) TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation. J Clin Invest 127:3313-3326 |
| Lyons-Cohen, Miranda R; Thomas, Seddon Y; Cook, Donald N et al. (2017) Precision-cut Mouse Lung Slices to Visualize Live Pulmonary Dendritic Cells. J Vis Exp : |
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