Irf5 As An Upstream Regulator Of Severe Steroid-Refractory Asthma

Severe, corticosteroid (CS)-refractory asthma is a significant problem both clinically and in terms of economic impact. A CS-responsive T helper-type 2 (Th2)/Type 2 response is a feature of milder asthma. However, we recently reported heightened airway type 1 (IFN-γ) and type 17 (IL-17) immune responses along with detectable Th2 response in u003e50% of clinically diagnosed severe asthma cases in adults in the context of CS treatment. In macrophages, the transcription factor IRF5 was previously shown to promote the expression of Type 1/17-inducing cytokines. However, its role in promoting the expression of these cytokines in dendritic cells (DCs), which would impact T helper cell differentiation, has not been studied. Thus, to determine the role of IRF5 in eliciting a CS-refractory severe asthma phenotype, we utilized our newly established model of severe asthma, in which IFN-γ plays an important role in increased airway hyperresponsiveness (AHR), and which is poorly responsive to CS mimicking human disease. Using WT and IRF5−/− mice subjected to the severe asthma model, we show that IRF5 is required to promote Th1 and Th17 immune responses and importantly, also plays a role in increased AHR. In the absence of IRF5, reduced Th1/Th17 responses were associated with decreased expression of the type-1/17-promoting cytokines IL-12 and IL-6 in lung DCs. Also, using bronchoalveolar lavage (BAL) cells, we detected higher IRF5 expression in human severe versus milder asthma. Therefore, IRF5 may represent a potential target for therapeutic intervention in CS-refractory human severe asthma with a strong Th1/Th17 immunobiologic component.