Phosphoinositide 3-Kinase ? Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity.

ABSTRACT: The C-type lectin receptor Dectin-2 can trigger the leukotriene C4 synthase-dependent generation of cysteinyl leukotrienes and the caspase-associated recruitment domain 9- and NF-?B-dependent generation of cytokines, such as IL-23, IL-6, and TNF-?, to promote Th2 and Th17 immunity, respectively. Dectin-2 activation also elicits the type 2 cytokine IL-33, but the mechanism by which Dectin-2 induces these diverse innate mediators is poorly understood. In this study, we identify a common upstream requirement for PI3K? activity for the generation of each Dectin-2-dependent mediator elicited by the house dust mite species, Dermatophagoides farinae, using both pharmacologic inhibition and small interfering RNA knockdown of PI3K? in bone marrow-derived dendritic cells. PI3K? activity depends on spleen tyrosine kinase (Syk) and regulates the activity of protein kinase C?, indicating that PI3K? is a proximal Syk-dependent signaling intermediate. Inhibition of PI3K? also reduces cysteinyl leukotrienes and cytokines elicited by Dectin-2 cross-linking, confirming the importance of this molecule in Dectin-2 signaling. Using an adoptive transfer model, we demonstrate that inhibition of PI3K? profoundly reduces the capacity of bone marrow-derived dendritic cells to sensitize recipient mice for Th2 and Th17 pulmonary inflammation in response to D. farinae Furthermore, administration of a PI3K? inhibitor during the sensitization of wild-type mice prevents the generation of D. farinae-induced pulmonary inflammation. These results demonstrate that PI3K? regulates Dectin-2 signaling and its dendritic cell function.

SUBMITTER: Lee MJ 

PROVIDER: S-EPMC4912906 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature