The Cytokines of Asthma

Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl4) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP+ cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl4 liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.

http://www.pnas.org/content/pnas/111/32/E3297.full.pdf

Origin of myofibroblasts in the fibrotic liver in mice

Innate Lymphoid Cells in Inflammation and Immunity

The epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as "alarmins" that are released by the barrier epithelium in response to external insults, these epithelial cell-derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. However, TSLP, IL-33, and IL-25 all regulate a broad spectrum of innate immune cell populations and are particularly potent in eliciting and activating type 2 innate lymphoid cells (ILC2s) that may act throughout allergic inflammation. Recent data suggest that a TSLP/ILC axis may mediate steroid resistance in asthma. Recent identification of memory Th2 cell subsets that are characterized by high receptor expression for TSLP, IL-33, and IL-25 further supports a role for these cytokines in allergic exacerbations. There is therefore growing interest in developing biologics that target TSLP, IL-33, and IL-25. This Review provides an overview of TSLP, IL-33, and IL-25 and the development of blocking antibodies that target these epithelial cell-derived cytokines.

/pdf/epithelial-cell-derived-cytokines-more-than-just-signaling-1jwegfjflt.pdf

Epithelial cell–derived cytokines: more than just signaling the alarm

Airway epithelial regulation of pulmonary immune homeostasis and inflammation.

Background Overexpression of the transforming growth factor β family signalling molecule smad2 in the airway epithelium provokes enhanced allergen-induced airway remodelling in mice, concomitant with elevated levels of interleukin (IL)-25. Objective We investigated whether IL-25 plays an active role in driving this airway remodelling. Methods Anti-IL-25 antibody was given to mice exposed to either inhaled house dust mite (HDM) alone, or in conjunction with an adenoviral smad2 vector which promotes an enhanced remodelling phenotype. Results Blocking IL-25 in allergen-exposed mice resulted in a moderate reduction in pulmonary eosinophilia and levels of T helper type 2 associated cytokines, IL-5 and IL-13. In addition, IL-25 neutralisation abrogated peribronchial collagen deposition, airway smooth muscle hyperplasia and airway hyperreactivity in control mice exposed to HDM and smad2-overexpressing mice. IL-25 was shown to act directly on human fibroblasts to induce collagen secretion. Recruitment of endothelial progenitor cells to the lung and subsequent neovascularisation was also IL-25 dependent, demonstrating a direct role for IL-25 during angiogenesis in vivo. Moreover, the secretion of innate epithelial derived cytokines IL-33 and thymic stromal lymphopoietin (TSLP) was completely ablated. Conclusions In addition to modulating acute inflammation, we now demonstrate a role for IL-25 in orchestrating airway remodelling. IL-25 also drives IL-33 and TSLP production in the lung. These data delineate a wider role for IL-25 in mediating structural changes to the lung following allergen exposure and implicate IL-25 as a novel therapeutic target for the treatment of airway remodelling in asthma.

https://thorax.bmj.com/content/thoraxjnl/68/1/82.full.pdf

Devika Sawant

Papers

IL-25 drives remodelling in allergic airways disease induced by house dust mite

in the ischemic rat lung attenuates bronchial angiogenesis 2 Inhibition of CXCR