Allergic asthma is a chronic inflammatory disease of the airways characterized by a type 2-high adaptive immune response towards common aeroantigens such as dust mite, pollen and animal dander. Despite the advances made towards translation of various biologics into the clinic, the limited efficacy of these therapies in certain populations, combined with the ineligibility of some patients for treatment (clinically or economically), have led to the continued need for the development of more widely effective allergic asthma therapies. Our lab has identified lectin mannose-binding 1 (LMAN1) as a novel receptor for house dust mite (HDM) and showed that in vitro, LMAN1 downregulated inflammatory NF-κB signaling in response to this allergen. Mechanistically, we demonstrated that LMAN1 interacted with FcRγ in dendritic cells (DCs) and recruited the negative regulator SHP1. These data suggest that LMAN1 acts as a negative regulator of the inflammatory response to HDM. To understand the in vivo relevance of this finding, we subjected LMAN1 knockout (KO) mice and wild type (WT) littermate controls to a model of HDM-induced allergic asthma. Surprisingly, we found that loss of LMAN1 led to opposing effects on airway hyperreactivity which were dependent on the sex of the mice. Female LMAN1 KO mice showed increased AHR, while male KO mice showed the opposite trend compared with their WT counterparts. We further characterized features of the HDM-induced inflammatory response which could explain these sex-dependent differences. Overall, this work provides the first mechanistic insights into potential signaling functions mediated by LMAN1 and also illuminates the complexity of the loss of LMAN1 in vivo.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2927 |
| Date | 01 January 2023 |
| Creators | Swaby, Lindsay |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
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