P2Y6 signaling in alveolar macrophages prevents leukotriene-dependent type 2 allergic lung inflammation.

Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific P2Y6 receptors that can be blocked by off-target effects of CysLT1R antagonists. Sensitizing intranasal doses of an extract from the house dust mite Dermatophagoides farinae (Df) sharply increased the levels of UDP detected in bronchoalveolar lavage fluid of mice. Conditional deletion of P2Y6 receptors before sensitization exacerbated eosinophilic lung inflammation and type 2 cytokine production in response to subsequent Df challenge. P2Y6 receptor signaling was necessary for dectin-2-dependent production of protective IL-12p40 and Th1 chemokines by alveolar macrophages, leading to activation of NK cells to generate IFN-γ. Administration of CysLT1R antagonists during sensitization blocked UDP-elicited potentiation of IL-12p40 production by macrophages in vitro, suppressed the Df-induced production of IL-12p40 and IFN-γ in vivo, and suppressed type 2 inflammation only in P2Y6-deficient mice. Thus, P2Y6 receptor signaling drives an innate macrophage/IL-12/NK cell/IFN-γ axis that prevents inappropriate allergic type 2 immune responses on respiratory allergen exposure and counteracts the Th2 priming effect of CysLT1R signaling at sensitization. Targeting P2Y6 signaling might prove to be a potential additional treatment strategy for allergy.

Lipid mediators and allergic diseases.

OBJECTIVE: To review the basic science and translational relevance of lipid mediators in the pathobiology of allergic diseases. DATA SOURCES: PubMed was searched for articles using the key terms lipid mediator, prostaglandin, prostanoid, leukotriene, thromboxane, asthma, and allergic inflammation. STUDY SELECTIONS: Articles were selected based on their relevance to the goals of this review. Articles with a particular focus on clinical and translational aspects of basic science discoveries were emphasized. RESULTS: Lipid mediators are bioactive molecules generated from cell membrane phospholipids. They play important roles in many disease states, particularly in inflammatory and immune responses. Lipid mediators and their receptors are potentially useful as diagnostic markers of disease and therapeutic targets. CONCLUSIONS: Several useful therapeutic agents have been developed based on a growing understanding of the lipid mediator pathways in allergic disease, notably the cysteinyl leukotriene receptor type 1 antagonists and the 5-lipoxygenase inhibitor, zileuton. Additional receptor agonists and antagonists relevant to these pathways are in development, and it is likely that future pharmacologic treatments for allergic disease will become available as our understanding of these molecules continues to evolve.

Downregulation of key early events in the mobilization of antigen-bearing dendritic cells by leukocyte immunoglobulin-like Receptor B4 in a mouse model of allergic pulmonary inflammation.

Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) null mice have an exacerbated T helper cell type 2 (Th2) immune response and pulmonary inflammation compared with Lilrb4(+/+) animals when sensitized intranasally with ovalbumin (OVA) and low-dose lipopolysaccharide (LPS) followed by challenge with OVA. Moreover, OVA-challenged Lilrb4(-/-) mice exhibit greater migration of antigen (Ag)-bearing dendritic cells (DCs) to lymph nodes and accumulation of interleukin 4- and interleukin 5-producing lymph node lymphocytes. The main objective of this study was to determine how the absence of LILRB4 leads to a greater number of DCs in the lymph nodes of Ag-challenged mice and increased lung Th2 inflammation. Mice were sensitized intranasally with PBS alone or containing OVA and LPS; additional cohorts were subsequently challenged with OVA. Expression of chemokine (C-C motif) ligand 21 (CCL21) in the lung was assessed immunohistologically. OVA ingestion and expression of LILRB4 and chemokine (C-C motif) receptor 7 (CCR7) were quantified by flow cytometry. Inhalation of OVA and LPS induced upregulation of LILRB4 selectively on lung Ag-bearing DCs. After sensitization and challenge, the lung lymphatic vessels of Lilrb4(-/-) mice expressed more CCL21, a chemokine that directs the migration of DCs from peripheral tissue to draining lymph nodes, compared with Lilrb4(+/+) mice. In addition, lung DCs of challenged Lilrb4(-/-) mice expressed more CCR7, the CCL21 receptor. The lungs of challenged Lilrb4(-/-) mice also contained significantly greater numbers of CD4+ cells expressing interleukin-4 or interleukin-5, consistent with the greater number of Ag-bearing DCs and Th2 cells in lymph nodes and the attendant exacerbated Th2 lung pathology. Our data establish a new mechanism by which LILRB4 can downregulate the development of pathologic allergic inflammation: reduced upregulation of key molecules needed for DC migration leading to decreases in Th2 cells in lymph nodes and their target tissue.