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Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias
Marc Gauthier, … , Sally E. Wenzel, Anuradha Ray
Marc Gauthier, … , Sally E. Wenzel, Anuradha Ray
Published July 6, 2017
Citation Information: JCI Insight. 2017;2(13):e94580. https://doi.org/10.1172/jci.insight.94580.
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Research Article Immunology Pulmonology

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

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Abstract

We previously showed that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be appreciated in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. We hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1high asthma and CS unresponsiveness. We show high levels of CXCL10 mRNA closely associated with IFNG levels in the BAL cells of 50% of severe asthmatics and also in the airways of mice subjected to a severe asthma model, both in the context of high-dose CS treatment. The inability of CS to dampen IFNG or CXCL10 expression was not because of impaired nuclear translocation of the glucocorticoid receptor (GR) or its transactivational functions. Rather, in the presence of CS and IFN-γ, STAT1 and GR were recruited on critical regulatory elements in the endogenous CXCL10 promoter in monocytes, albeit without any abatement of CXCL10 gene expression. High CXCL10 gene expression was also associated with a mast cell signature in both humans and mice, CXCR3 being also expressed by mast cells. These findings suggest that the IFN-γ–CXCL10 axis plays a central role in persistent type 1 inflammation that may be facilitated by CS therapy through GR-STAT1 cooperation converging on the CXCL10 promoter.

Authors

Marc Gauthier, Krishnendu Chakraborty, Timothy B. Oriss, Mahesh Raundhal, Sudipta Das, Jie Chen, Rachael Huff, Ayan Sinha, Merritt Fajt, Prabir Ray, Sally E. Wenzel, Anuradha Ray

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Figure 4

IFN-γ does not suppress the cellular response to CS.

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IFN-γ does not suppress the cellular response to CS.
(A) Human PBMCs wer...
(A) Human PBMCs were treated with IFN-γ, Dexamethasone (Dex), or both for 1 hour and were analyzed by imaging cytometry using an ImageStreamX Mark II instrument. Gating on monocytes was accomplished using cell area versus aspect ratio, with verification by CD14 staining. Similarity scores (the degree of glucocorticoid receptor [GR] and nuclear counterstain, DRAQ5 colocalization) were calculated for each condition using the Amnis IDEAS software nuclear translocation wizard. Using visual assessment of cytoplasmic versus nuclear GR (representative examples shown) and comparing untreated with treated samples, final gating was set on the similarity score versus normalized frequency plots. Shown are images of brightfield (channel 1), nuclear (DRAQ5) staining (channel 11), GR staining (channel 2), and merged images of nuclear and GR staining (channels 11 and 2). The values shown are the percentage of the monocyte population in which GR has been translocated to the nucleus. (B) Human monocytes were treated as in A and harvested after 3 hours for analysis of DUSP1 mRNA levels (data pooled from 2 separate experiments). (C) THP-1 cells underwent nucleofection with a plasmid containing a glucocorticoid response element (GRE) linked to the luciferase gene. Luciferase activity detected by a luminometer was normalized to Renilla luciferase activity used as a transfection control (data shown representative of 2 separate experiments). Error bars show ± SEM, *P < 0.05, **P < 0.01 Tukey’s posthoc test (B–D).

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