The common γ-chain cytokine IL-7 promotes immunopathogenesis during fungal asthma

Abstract

Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1β). Intriguingly, IL-7 administration also increased IL-22, which we have previously reported to drive immunopathogenic responses in experimental fungal asthma. Employing IL22R26R reporter mice, we identified γδ T cells, iNKT cells, CD4 T cells and ILC3s as sources of IL-22 during fungal asthma; however, only iNKT cells were significantly increased after IL-7 administration. IL-7-induced immunopathogenesis required both type 2 and IL-22 responses. Blockade of IL-7Rα in vivo resulted in attenuated IL-22 production, lower CCL22 levels, decreased iNKT cell, CD4 T-cell and eosinophil recruitment, yet paradoxically increased dynamic lung resistance. Collectively, these results suggest a complex role for IL-7 signaling in allergic fungal asthma.

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation

“…In that report, Luminex-based analysis identified multiple cytokine, chemokine, and growth factors that were significantly elevated in BALF from fungal-sensitized asthmatics (10). Among these was IL-1RA, with regression analysis revealing that IL-1RA had a negative correlation with PC20 (i.e., higher IL-1RA levels correlated with lower PC20), which may suggest a role for IL-1RA in immunopathogenesis during fungal asthma (10). Alternatively, elevated IL-1RA levels could serve as a biomarker of lung function decline during fungal asthma.…”

“…Human asthmatics sensitized to fungi have elevated IL-1α and IL-1β levels in BAL and sputum. We have recently reported that human asthmatics sensitized to fungi (National Heart Lung and Blood Institute's Severe Asthma Research Program [SARP] cohorts 1 and 2) have more severe disease as determined by multiple lung function (forced expiratory volume in 1 second, FEV 1 ; concentration of methacholine producing 20% drop in FEV 1 , PC20) and atopic measurements (serum IgE, blood eosinophils numbers) (10). In that report, Luminex-based analysis identified multiple cytokine, chemokine, and growth factors that were significantly elevated in BALF from fungal-sensitized asthmatics (10).…”

“…We have recently reported that human asthmatics sensitized to fungi (National Heart Lung and Blood Institute's Severe Asthma Research Program [SARP] cohorts 1 and 2) have more severe disease as determined by multiple lung function (forced expiratory volume in 1 second, FEV 1 ; concentration of methacholine producing 20% drop in FEV 1 , PC20) and atopic measurements (serum IgE, blood eosinophils numbers) (10). In that report, Luminex-based analysis identified multiple cytokine, chemokine, and growth factors that were significantly elevated in BALF from fungal-sensitized asthmatics (10). Among these was IL-1RA, with regression analysis revealing that IL-1RA had a negative correlation with PC20 (i.e., higher IL-1RA levels correlated with lower PC20), which may suggest a role for IL-1RA in immunopathogenesis during fungal asthma (10).…”

“…With regard to SAFS specifically, studies comparing genetic susceptibility in individuals with atopic asthma vs. individuals with SAFS have identified the pattern recognition receptors (PRRs) TLR3, TLR9, and Dectin-1 and the cytokines/chemokines IL-10, CCL2, and CCL17 as candidates for therapeutic development (9). We have also recently identified IL-7 as a potential immunopathogenic factor in human asthma and experimental fungalassociated allergic airway inflammation (10). In a study of pediatric asthmatics, those with SAFS demonstrated higher IgE levels and required higher usage of maintenance oral steroids to achieve similar clinical Severe asthma with fungal sensitization (SAFS) defines a subset of human asthmatics with allergy to 1 or more fungal species and difficult-to-control asthma.…”

Role of Common γ-Chain Cytokines in Lung Interleukin-22 Regulation after Acute Exposure to Aspergillus fumigatus

“…T and B lymphocytes, as well as innate-like lymphocytes, express the common ␥-chain cytokine receptor, and cytokines in this family are critical for generation, development, or homeostasis of these cell types (36,38). In addition, we have recently identified a role for the common ␥-chain cytokine IL-7 in iNKT-and IL-22-associated immunopathogenesis during A. fumigatus-associated fungal asthma (39). To this end, we examined the impact of common ␥-chain cytokines on lung IL-22 induction and clearance of A. fumigatus after acute exposure.…”