IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice

Abstract

Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ- and IL-17-producing CD4+ T cells and IRF5-/- mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics.

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…Furthermore, using our mouse model of SA, we showed that elevated IFN-γ leads to high airway resistance, increased inflammatory infiltrates in the lung, and poor response to CS treatment (5). We have also recently documented a higher level of expression of the transcription factor IRF5 in the lungs of severe asthmatics compared with that in their milder counterparts and demonstrated a critical role for this molecule, expressed by lung DCs and macrophages, in regulation of the Th1/IFN-γ response in our SA model (37). In the present study, we asked whether IFN-γ contributes to CS unresponsiveness by focusing on its downstream target CXCL10, the best described of several CXCR3 ligands that serve to recruit Th1 cells as well as mast cells and eosinophils to the site of inflammation (11).…”

“…When viewed in aggregate, the IRF5/IFN-γ/CXCL10 pathway appears to be steroid refractory (5,37). Based on ChIP data, once established, this pathway may actually be perpetuated by chronic steroid therapy through interactions between GR and STAT1 on target sites in the CXCL10 promoter.…”

Combined administration of anti‐IL‐13 and anti‐IL‐17A at individually sub‐therapeutic doses limits asthma‐like symptoms in a mouse model of Th2/Th17 high asthma

“…However, it is increasingly clear that the Th2 paradigm is insufficient to explain the full spectrum of asthma severity. For example, induction of Th1‐associated immune responses, with or without concomitant Th2 responses, are associated with more severe airway pathology and increased resistance to common therapeutic approaches in mouse models of asthma and in humans . Similarly, multiple lines of evidence suggest that induction of a mixed Th2/Th17 cytokine profile is associated with the development of more severe disease pathogenesis.…”

T cells in severe childhood asthma

“…Two additional reports identify molecules that may be pivotal to CS resistance in established Th1‐driven disease. The first study implicated the transcription factor IRF5, which is expressed in BAL cells of adults with severe asthma . This molecule was previously found to promote transcription of IL6, IL12 and IL23p19 in human macrophages and induction of Th1/Th17 responses in co‐cultured CD4 + T cells .…”

“…This molecule was previously found to promote transcription of IL6, IL12 and IL23p19 in human macrophages and induction of Th1/Th17 responses in co‐cultured CD4 + T cells . In a severe asthma model, knockout of Irf5 in dendritic cells attenuated Th1 and Th17 responses while enhancing Th2 responses and rendering the T cell response sensitive to CS . The other study explored the potential link between Th1 cells and CS resistance, based on the presence of Th1 cells in the airways of half of severe asthmatic adults on high‐dose therapy.…”