Exposure to the mold Aspergillus fumigatus may result in a range of conditions from one of the worst forms of asthma, allergic bronchopulmonary aspergillosis (ABPA), to one of the most lethal fungal infections known, invasive aspergillosis (IA). We have previously reported a comprehensive role for the beta-glucan receptor Dectin-1 and Dectin-1 mediated IL-22 production in innate immune responses after A. fumigatus exposure. Examining IL-22 cell sources using novel IL-22 reporter mice, we have discovered kinetic production of IL-22 by multiple cell types. We have also discovered that a member of the common ?-chain cytokine family is required for lung IL-22 production whereas specific members of the IL-1/TLR family negatively regulate IL-22. Mechanistically, we have found that this negative regulation of IL-22 is associated with downregulation of COX- 2 mediated pathways that promote IL-22. We have previously reported that IL-22 deficient mice had impaired levels of soluble factors that mediate antifungal immunity. However, we excluded several known IL-22 associated antimicrobial factors as mediators of the IL-22 dependent antifungal response. In a pilot proteomic analysis of lung lavage fluid, we identified the acute phase proteins that mediate antifungal defense via the regulation of iron availability. Together, our proposed studies will identify cell types producing IL-22, what pathways regulate the production of IL-22 and how IL-22 mediates antifungal defense. A better understanding of IL-22 biology will better inform the development of therapeutics to treat the wide range of conditions associated with A. fumigatus exposure.
The specific aims of the proposal are: (1) Identify cell sources of IL-22 and the magnitude by which different common ?-chain cytokines affect the IL-22 response during acute A. fumigatus lung infection, (2) Determine arachidonic acid metabolism pathways promoting lung IL-22 responses during acute A. fumigatus lung infection and whether/how these are regulated by specific IL-1/TLR family members and (3) Identify IL-22 dependent antifungal factors during acute A. fumigatus lung infection.
This proposal seeks to identify cell types in the lung that produce the cytokine IL-22, what pathways positively and negatively regulate the production of IL-22 and how IL-22 mediates antifungal defense in the lung. A better understanding of IL-22 biology will better inform the development of therapeutics to treat the wide range of conditions and the different lung diseases associated with Aspergillus fumigatus exposure.
|Patel, Dhiren F; Peiró, Teresa; Shoemark, Amelia et al. (2018) An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness. Sci Transl Med 10:|
|Reeder, Kristen M; Dunaway, Chad W; Blackburn, Jonathan P et al. (2018) The common ?-chain cytokine IL-7 promotes immunopathogenesis during fungal asthma. Mucosal Immunol 11:1352-1362|
|Garth, Jaleesa M; Mackel, Joseph J; Reeder, Kristen M et al. (2018) Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure. Infect Immun 86:|
|Hastie, A T; Steele, C; Dunaway, C W et al. (2018) Complex association patterns for inflammatory mediators in induced sputum from subjects with asthma. Clin Exp Allergy 48:787-797|
|Reeder, Kristen M; Mackel, Joseph J; Godwin, Matthew S et al. (2018) The role of common ?-chain cytokines in lung IL-22 regulation after acute exposure to Aspergillus fumigatus. Infect Immun :|
|Hough, Kenneth P; Trevor, Jennifer L; Strenkowski, John G et al. (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54-64|
|Garth, Jaleesa M; Steele, Chad (2017) Innate Lung Defense during Invasive Aspergillosis: New Mechanisms. J Innate Immun 9:271-280|
|Garth, Jaleesa M; Reeder, Kristen M; Godwin, Matthew S et al. (2017) IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection. J Immunol 199:2140-2148|