IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice
Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray
Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray
View: Text | PDF
Research Article Pulmonology

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.

Authors

Timothy B. Oriss, Mahesh Raundhal, Christina Morse, Rachael E. Huff, Sudipta Das, Rachel Hannum, Marc C. Gauthier, Kathryn L. Scholl, Krishnendu Chakraborty, Seyed M. Nouraie, Sally E. Wenzel, Prabir Ray, Anuradha Ray

×

Figure 4

IRF5–/– DCs with deficiency in IL-12 and IL-6 production have reduced capacity to promote T cell IFN-γ and IL-17A production.

Options: View larger image (or click on image) Download as PowerPoint
IRF5–/– DCs with deficiency in IL-12 and IL-6 production have reduced c...
Lymph nodes were harvested 1 day following sensitization with OVA + cyclic diguanosine monophosphate (c-di-GMP) on days 1, 3, and 5. (A) Total lymph node cells were restimulated in vitro for 72 hours with OVA. The levels of IFN-γ and IL-17A in the culture supernatants were assessed by ELISA (n = 3 WT, 4 IRF5–/– mice). (B) Increasing numbers of lymph node migratory DCs (migDCs) purified by cell sorting as in Figure 3 were cocultured with naive (CD62LhiCD44lo) spleen OT-II TCR-transgenic CD4+ T cells similarly purified by cell sorting in the presence of OVA (left panel) or with increasing concentration of recombinant murine IL-12 (right panel) and secreted IFN-γ was measured after 72 hours. Data are the mean ± SEM of triplicate cultures of pooled cells from 3 to 5 mice per group. ****P ≤ 0.0001 by the Mann-Whitney U test. Each experiment was performed twice independently.