PlexinD1 deficiency in CD11c+ dendritic cells exacerbates airway hyperresponsiveness and enhances IgE and mucus production in allergic asthma

Abstract

Dendritic cells (DC) play a crucial role in regulating allergic asthma. We have demonstrated that the absence of semaphorin3E (Sema3E) exacerbates asthma features in acute and chronic asthma models. However, the role of plexinD1 in these events, especially in DC is unknown. Therefore, we investigated the role of plexinD1 in CD11c+ DC in the HDM model of asthma. CD11c+ DC-specific plexinD1 knockout mice and wild-type mice were subjected to HDM acute allergen protocol. Airway hyperresponsiveness (AHR) parameters were measured using the FlexiVent ventilator. Lung tissue and bronchoalveolar lavage fluid (BALF) were processed by flow cytometry. Cytokines and antibodies were measured using mesoscale and ELISA. Collagen deposition and mucus production were visualized by histological staining, and associated genes were investigated using Real-time PCR. We showed that DC-specific plexinD1 knockout mice exhibited exacerbated airway hyperresponsiveness, including increased airway resistance and tissue elastance. These mice displayed enhanced levels of mucus production and collagen gene expression compared to wild-type mice. These events were accompanied by enhanced recruitment of conventional DCs, specifically CD11b+ cDC2, into the lungs and higher levels of total and HDM-specific serum IgE in CD11cPLXND1 KO compared to wild-type counterparts. Mechanistically, a significantly higher level of IgE in the co-culture of B-DCs isolated from CD11cPLXND1 KO mice compared to DCs isolated from wild-type mice. Overall, our data reveals that the Sema3E-plexinD1 signalling pathway in CD11c+ DC is critical in modulating asthma features. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/557276v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@170c121org.highwire.dtl.DTLVardef@1979dddorg.highwire.dtl.DTLVardef@fd547borg.highwire.dtl.DTLVardef@1b5726a_HPS_FORMAT_FIGEXP M_FIG C_FIG