Asthma and allergies affect an estimated 235 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Children are a major and growing population of asthma and aller- gy sufferers, but the precipitating factors are not known. Our current understanding of these diseases demon- strates that Th2 cells play a major role in the type 2 inflammatory response characteristic of these diseases. Recently, Th17 cell responses have also been implicated in asthma, especially in the most severe patients. However, the factors that induce T cells to differentiate towards a Th2 phenotype, and not a Th17 phenotype, remain one of the important unresolved problems in these diseases. Dendritic cells (DCs) are antigen- presenting cells central to the induction of Th2 differentiation. However the molecular mechanisms by which Th2-skewing DCs (DCTh2) develop has remained controversial. Through studies by our group and others, the transcription factor IRF4 has emerged as a key regulator of DCTh2 development. We found that two distinct al- lergic stimuli, immune complexes and house dust mite extract (HDM), can signal through FcR?-associated re- ceptors to induce bone marrow-derived DCs (BMDC) to upregulate IRF4, and that IRF4 expression is neces- sary for the BMDCs production of the cytokines IL-33 and IL-10. Further, HDM-induced type 2 inflammation and Th2 responses are reduced in mice lacking expression of IRF4 in CD11c+ DCs. Together, these data identify a mechanism whereby Th2 stimuli signal through FcR?-associated receptors on DCs to induce IRF4 expression and IL-33 and IL-10 production. However, the in vivo mechanisms by which DC expression of IRF4 promotes type 2 inflammation, and the relevance of these studies to human asthma, remain unknown. The overall hypothesis of this project is that through the upregulation of IRF4 and its downstream mediators, DCs induce the development of type 2 inflammation and tissue resident memory (TRM) Th2 cells in the lungs of asthmatics and mice with experimental asthma. To address our hypothesis, we propose to determine 1) the mechanisms by which IRF4 expression by DCs regulate type 2 inflammation and the development of resident memory Th2 cells, 2) the role of downstream effectors of IRF4 expression in DCs in type 2 inflammation and memory responses, and 3) whether IRF4 expression by human lung DCs is affected by asthma status and the asthmatic cytokine milieu. Understanding the mechanisms by which DCs promote asthma-type inflammation is key to the development of new targets for therapeutics. IRF4, or its downstream effector molecules, are attrac- tive candidates for this purpose since IRF4+ DCs have been implicated in both Th2 and Th17 asthma pheno- types. Through the proposed translational study, we seek to reveal how these IRF4+ DCs function to promote type 2 inflammation in mouse models of experimental asthma and in human asthma.
The dramatic increase in both the prevalence and severity of asthma in the United States over the past 50 years has led to increased research on the pathogenesis of the disease. Yet fundamental questions still re- main. The goal of these studies is to investigate the regulation of the asthmatic inflammatory response to elu- cidate novel targets for therapeutic intervention.
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