In humans, increased expression of IL-33 in the nuclei of airway epithelial cells has been reported in patients with asthma [ 41] and chronic obstructive pulmonary disease (COPD) [ 20••]. Interestingly, IL-33 expression was traceable to a subset of airway epithelial cells with progenitor function [ 20••]. Inducible PR-171 price expression of IL-33 in mouse tissues has also been observed outside the lungs, for instance in hepatocytes during acute hepatitis [ 42], and in endothelial cells from the inflamed colon during colitis [ 37•].

IL-33 is generally not expressed in CD45+ hematopoietic cells under basal conditions, but it can be induced in macrophages and dendritic cells during allergic inflammation and infection [19, 40• and 43]. However, IL-33 levels in CD45+ cells appear to be at least 10 fold lower than those found in CD45− epithelial cells [20••, 25 and 40•], and the protein was not detected in F4/80+ alveolar macrophages in lung tissue sections during allergic inflammation [23] or infection [16••]. In addition, recent analyses in a mouse

model of allergic rhinitis revealed that tissue-derived IL-33, rather than immune-cell derived IL-33, is crucial for induction of allergic inflammation [44]. Biologically active full length IL-33 can be released in the extracellular space after cell damage (necrotic cell death) or mechanical injury [45 and 46]. IL-33 was thus proposed to function as a novel alarmin (intracellular alarm signal released upon cell injury) to alert the immune system of tissue damage following trauma or infection [36, 37•, 45 and 46]. IL-33 is likely to be a very good alarm Roxadustat signal because, due to its constitutive expression Adenosine in normal tissues, it is ready to be released at any time, for ‘alarming’ ILC2s and other immune cells (Figure 2). Environmental allergens, such as ragweed pollen and A. alternata, have been shown to induce the rapid (∼1 hour) release of IL-33 in nasal and bronchoalveolar lavage (BAL) fluids, respectively [ 29••, 47 and 48]. This increase of IL-33 protein in extracellular fluids was associated

with reduced staining for IL-33 in the nuclei of nasal epithelial cells [ 29••] and ATII pneumocytes [ 48], suggesting extracellular release of preformed nuclear IL-33. Many airborne allergens have intrinsic protease activities [ 26, 28• and 48], and allergen proteases have been shown to play a role in the rapid increase of IL-33 levels in BAL fluids after intranasal administration [ 26 and 48]. Allergens and allergen proteases can cause breakdown of epithelial barriers in vivo and may thus induce the release of IL-33 through cellular necrosis. However, allergen exposure also leads to extracellular accumulation of danger signals, such as ATP and uric acid, which appear to induce the extracellular release of IL-33 without apparent cell death [ 20••, 28• and 47].