Cell surface LMAN1 as a General Sensor and Negative Regulator of Mannosylated Aeroallergens

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Sensitization to allergens early in life is a risk factor for the subsequent development of asthma. For sensitized individuals, severity in asthma symptoms also correlates with the level of exposure to allergens. Although the downstream adaptive immune responses resulting from allergen exposure as well as the relationship of these responses to asthmatic symptoms are well understood, knowledge of the mechanisms by which allergens are initially sensed or recognized in the airway and how such early events shape the resulting disease course are still lacking. The long-term objective of this project is to characterize and understand the function of the protein LMAN1 in serving as a receptor for mannosylated aeroallergens. LMAN1 (Lectin, Mannose Binding 1) was identified as a candidate receptor for house dust mite using an unbiased receptor capture approach. Subsequent in vitro biochemical analysis indicates that this lectin can bind other unrelated allergens as well. LMAN1 is a mannose binding lectin which is primarily recognized to act as a cargo transporter between the ER, ERGIC, and Golgi compartments. Our preliminary data indicates that LMAN1 can also exist on the surface of cells and is expressed on both dendritic cells (DCs) and airway epithelial cells (AECs) in the lung. We additionally have evidence to suggest that LMAN1 downregulates the immune response against allergens, potentially through modulation of NF-kB activity. In this proposal, we seek to determine whether recognition of mannosylated aeroallergens for downregulation of allergic responses is a general function of LMAN1 through the use of biochemical and cellular binding assays and by subjecting WT and LMAN1 KO mice to models of allergic airway inflammation. Furthermore, we aim to determine the molecular mechanisms underlying the ability of LMAN1 to regulate allergic responses. We will use WT or LMAN1 KO DCs and AECs to investigate the signaling events induced through four pathways potentially utilized by LMAN1 to modulate NF- kB activity. Understanding whether LMAN1 can serve as a general sensor and negative regulator of allergic responses and the molecular mechanisms by which this receptor carries out its regulatory function will provide the basis for consideration of LMAN1 as a potential molecular drug target. If successful, this will, in turn, lead to future studies identifying and testing the efficacy of LMAN1-targeted therapies for modulation of allergic airway inflammation.