High IFN-γ and low SLPI mark severe asthma in mice and humans

Abstract

Results SA subjects harbor more IFN-γ + CD4+ T cells in their airways compared with MMA subjects. A total of 66 subjects, 33 classified with MMA and 33 classified with SA, were included in this study; details of patient characteristics are included in Table 1. Of note, biological samples, such as cells in BAL fluid used for differential cell counts and cytokine expression, were analyzed from a subset of these subjects based on availability, as described in each figure legend. Since the recovery of BAL Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng -/-mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra -/-mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…More specifically, combined LPS/IFN-g-induced IL-27 production has been linked to steroidresistant AHR (7)(8)(9)(10). A recent report has characterized and differentiated severe asthma from mild-moderate asthma by high level of IFN-g in lung tissues and BAL fluid, where IFN-g was found to promote steroid-refractory AHR (7).…”

“…More specifically, combined LPS/IFN-g-induced IL-27 production has been linked to steroidresistant AHR (7)(8)(9)(10). A recent report has characterized and differentiated severe asthma from mild-moderate asthma by high level of IFN-g in lung tissues and BAL fluid, where IFN-g was found to promote steroid-refractory AHR (7). In this study, combined LPS/IFN-g induced steroid resistance in IL-27 production and methacholine-induced AHR, and andrographoilde was able to restore sensitivity of dexamethasone in inhibiting IL-27 production and AHR, probably via upregulation of nuclear HDAC2 level and total HDAC activity.…”

“…Acute exacerbations of asthma, often triggered by respiratory bacterial or viral infections, are critical clinical problems for asthma management and treatment. High levels of LPS and Th1 cytokine IFN-g have been detected in the airways of asthmatics, which are often correlated with asthma severity (3)(4)(5)(6)(7). LPS and IFN-g are two key mediators for exacerbative inflammatory responses and the decrease in sensitivity to steroid in experimental models of asthma (7)(8)(9).…”

“…High levels of LPS and Th1 cytokine IFN-g have been detected in the airways of asthmatics, which are often correlated with asthma severity (3)(4)(5)(6)(7). LPS and IFN-g are two key mediators for exacerbative inflammatory responses and the decrease in sensitivity to steroid in experimental models of asthma (7)(8)(9). Macrophage-derived IL-27 has been shown to be upregulated by LPS/IFN-g and mediate LPS/IFN-g-induced steroid-resistant AHR, as neutralizing IL-27 Ab significantly attenuated this response (10).…”

Novel approaches to the management of noneosinophilic asthma

“…immune responses and low secretory leukocyte protease inhibitor expression (SLPI) in airway epithelial cells with airway hyperresponsiveness [Raundhal et al 2015]. Neutrophils are a potential source of oxygen free radicals and enzymes and their ability to activate other airway cell types [Futosi et al 2013].…”