We recently reported the identification of a mechanism by which dendritic cells (DCs) influence T helper cells to mount allergic airway inflammation in the lung. The allergen house dust mite caused dual upregulation of c-kit and its ligand, stem cell factor (SCF), on DCs stimulating production of interleukin-6 (IL-6) and expression of the Notch ligand, Jagged-2, but downregulated IL-12 production. This, in turn, promoted Th2/Th17 development but inhibited Th1 differentiation. DCs lacking functional c-kit were unable to produce IL-6 or express Jagged-2. When adoptively transferred into mice, unlike their wild-type counterparts, DCs expressing mutant c-kit were unable to induce a robust Th2/Th17 response or allergic airway inflammation in the recipient mice. DCs generated from mice with defects in PI3 kinase secreted lower levels of IL-6 upon stimulation with a mucosal adjuvant. These findings collectively lead us to hypothesize that the c-kit/Jagged-2/IL-6 pathway in DCs plays an important role in the promotion of allergic airways disease by regulating cytokine (IL-6/IL-12) balance and expression of Jagged-2 that together influence the immune response to allergens. Disabling c-kit in DCs would help control asthma in response to particular allergens that promote this pathway. To address these hypotheses we will:
Aim I. Characterize the effect of common allergens on c-kit/Jagged-2/IL-6 expression in lung DCs and the consequence of blockade of c-kit function with a modified form of Gleevec.
Aim II. Generate transgenic mice inducibly expressing a dominant-negative mutant of c-kit in DCs to investigate effects on the asthma phenotype in response to the above allergens.
The goal of this project is to understand the role of a cell surface molecule, c-kit, in promoting allergic immune response to various common allergens using murine models of allergic asthma.
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|Oriss, Timothy B; Krishnamoorthy, Nandini; Raundhal, Mahesh et al. (2014) Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response. J Immunol 192:5471-5475|
|Poe, S L; Arora, M; Oriss, T B et al. (2013) STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia. Mucosal Immunol 6:189-99|
|Krishnamoorthy, Nandini; Khare, Anupriya; Oriss, Timothy B et al. (2012) Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat Med 18:1525-30|