Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Although some degree of inflammation is required for protection, progressive inflammation may worsen disease and ultimately prevents pathogen eradication. To define molecular pathways leading to or diverting from pathogenic inflammation in infection, we resorted to dendritic cells (DCs), known to activate distinct signaling pathways in response to pathogens. We found that distinct intracellular pathways mediated the sensing of conidia and hyphae by lung DCs in vitro, which translate in vivo in the activation of protective Th1/Treg responses by conidia or inflammatory Th2/Th17 responses by hyphae. In vivo targeting inflammatory (PI3K/Akt/mTOR) or anti-inflammatory (STAT3/IDO) DC pathways by intranasally delivered small interfering RNA (siRNA) accordingly modified inflammation and immunity to infection. Thus, the screening of signaling pathways in DCs through a systems biology approach may be exploited for the development of siRNA therapeutics to attenuate inflammation in respiratory fungal infections and diseases.