Interleukin 25 promotes the initiation of proallergic type 2 responses

The molecular mechanisms underlying the initiation of innate and adaptive proallergic type 2 responses are not understood. Interleukin (IL) 25, a member of the IL-17 cytokine family, was recently reported (Owyang, A.M., C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, and D. Artis. 2006. J. Exp. Med. 203:843–849; Fallon, P.G., S.J. Ballantyne, N.E. Mangan, J.L. Barlow, A. Dasvarma, D.R. Hewett, A. McIlgorm, H.E. Jolin, and A.N. McKenzie. 2006. J. Exp. Med. 203:1105–1116) to be important in Th2 cell–mediated immunity to parasitic infection. However, the cellular source and targets of IL-25 are not well understood. We show that mouse IL-25 is expressed by lung epithelial cells as a result of innate immune responses to allergens. Transgenic overexpression of IL-25 by these cells leads to mucus production and airway infiltration of macrophages and eosinophils, whereas blockade of IL-25 conversely reduces the airway inflammation and Th2 cytokine production in an allergen-induced asthma model. In addition, IL-25, with a receptor more highly expressed in Th2 than other effector T cells, promotes Th2 cell differentiation in an IL-4– and signal transducer and activator of transcription 6–dependent manner. During early T cell activation, IL-25 potentiates expression of the nuclear factor of activated T cells c1 and JunB transcription factors, which possibly results in increased levels of initial IL-4 production, up-regulation of GATA-3 expression, and enhanced Th2 cell differentiation. Thus, IL-25 is a critical factor regulating the initiation of innate and adaptive proallergic responses

Protease Allergens Induce the Expression of IL-25 via Erk and p38 MAPK Pathway

Allergic diseases, including asthma, are characterized by T helper type 2 (Th2) cell-mediated inflammations, coupled with tissue infiltration by eosinophils. In this study, we demonstrate that multiple protease allergens, including papain and DerP1, efficiently induce interleukin (IL)-25 and thymic stromal lymphopoietin (TSLP) gene expression, and this phenomenon is dependent on the protease activities of these allergens. The IL-25 cytokine level in bronchial alveolar lavage (BAL) was also profoundly and significantly increased after treatment with papain. Additionally, the levels of Th2 cytokines were significantly increased, as compared to those in the OVA-only treatment group. The various protease allergens triggered the expression of IL-25 and TSLP mRNA in mouse lung epithelial cells (MLE12) and primary mouse lung epithelial cells; these effects were inhibited by the deactivation of the protease activity of papain. The allergen papain activates the ErK and p38 MAP pathways; the inhibition of these pathways, but not the NFκB or PI-3 kinase pathways, impairs the induction of IL-25 and TSLP expression by proteases. In this study, we demonstrate that the protease allergens induce IL-25 and TSLP via the MAP kinase signal pathways, and their protease activities are essential to this pathway

Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma.

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7(-/-) mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7(-/-) mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells

The role of IL -25 in allergic lung disease

Allergic asthma is a chronic inflammatory disease of the airways caused by dysregulated immune responses to allergens. Despite compelling evidence that Th2-mediated immune responses orchestrate the pathogenesis of asthma diseases, the mechanisms underlying their initiation remain elusive. IL-25 (IL-17E), a novel cytokine in the IL-17 family plays a unique role in regulating type-2 immune responses. However, its biological function in allergic asthma has not been elucidated. Here, we demonstrated that IL-25 initiates allergic reactions by bridging the innate and adaptive immune responses of allergic asthma. IL-25 mRNA expression was up-regulated in lung epithelial cells upon exposure to common allergens, and mice overexpressing IL-25 in lung epithelium displayed features of allergic asthma, including eosinophilia, and epithelial and goblet cell hyperplasia. Moreover, administration of an antagonistic antibody against IL-25 in a mouse model of allergic asthma attenuated airway inflammation and antigen-specific Th2 responses induced by endogenous IL-25. In searching for IL-25-responding cells, Th2 cells that expressed the highest levels of IL-17RB, the cognate receptor for IL-25, were found to be the potential target of IL-25. Indeed, we showed that IL-25 promoted the differentiation and effector functions of Th2 cells by inducing early IL-4 production through the activation of the transcription factors JUNB and NFATc1. Interestingly, we found that the enhanced Th2 differentiation mediated by IL-25 required signals induced by a heterodimeric receptor complex composed of both IL-17RB and IL-17RA. To further elucidate the cellular mechanisms by which IL-25 amplifies type-2 immune responses, mice overexpressing IL-17RB driven by the CD4 promoter were generated. T cells isolated from IL-17RB transgenic mice and cultured with IL-25 were prone to produce prodigious amounts of Th2 cytokines. In an experimental asthma model, CD4-IL-17RB transgenic mice exhibited allergic airway inflammation, demonstrating that IL-25 enhances Th2 polarization and effector functions, thereby leading to the exacerbation of allergic asthma. We also uncovered an additional function of IL-25 to induce the up-regulation of IL-9 in IL-17RB transgenic T cells independent of IL-4. Our findings provide a novel mechanism that initiates allergic asthma and may facilitate the development of therapeutic approaches for future immune-based therapies for allergic asthma

Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

Abstract The epithelial cell-derived cytokines IL-33 and IL-25 are important mediators in driving type-2 inflammation during C. neoformans infection. Nevertheless, the impact of these cytokines in regulating host T helper cell response during C. neoformans infection is still unclear. We observed that C. neoformans infection promoted a predominant increase of T helper cells that co-expressed IL-25 and IL-33 receptors within the lung during the late infection phase. A comparative transcriptomic analysis of effector T helper cells co-treated with IL-25 and IL-33 revealed a cooperative effect of these cytokines in promoting IL-13 gene expression. Without IL-25 receptor signaling, IL-33 treatment upregulated Th1-associated genes and genes associated with nucleotide metabolism. By contrast, IL-25 had a unique effect in enhancing type-2 cytokines IL-5 and IL-9 and chemokine CCL24, as well as genes in the pathways that are associated with L-arginine metabolisms. Interestingly, this pathogenic T helper cell population that expressed IL-25 and IL-33 receptors was greatly enriched in mice that were infected with high cryptococcal virulence and associated with fungal burdens in the brain. Therefore, our data further provide the additional function of IL-25 and IL-33 in potentiating cryptococcal brain dissemination

Regulation and function of adiponectin in the intestinal epithelial cells in response to Trichinella spiralis infection

Abstract Besides metabolic homeostasis regulation, adipokines are recently emerged as important players in regulating immunity and inflammation. Helminth infection has known to modulate circulating adipokine secretion; however, the regulation and function of adipokines in response to helminth infection is still unclear. Here, we investigated the regulation and function of adiponectin during T. spiralis infection. While there was no change in circulating level of adiponectin, we found an increased adiponectin, but not leptin expression in the small intestine. Interestingly, the intestinal adiponectin expression was strongly associated with the expression of epithelial cell-derived cytokines IL-25, IL-33, and TSLP following infection. Indeed, mice deficiency of IL-25 receptor exhibited no intestinal adiponectin induction upon helminth infection. Interestingly, IL-25-induced adiponectin modulated intestinal epithelial cell responses by enhancing occludin and CCL17 expression. Using LPS-induced intestinal epithelial barrier dysfunctions in a Caco-2 cell monolayer model, adiponectin pretreatment enhanced a Transepithelial electrical resistance (TEER) and occludin expression. More importantly, adiponectin pretreatment of Caco2 cells prevented T. spiralis larval invasion in vitro and its administration during infection enhanced intestinal IL-13 secretion and worm expulsion in vivo. Altogether, our data suggest that intestinal adiponectin expression induced by helminth infection through the regulation of IL-25 promotes worm clearance and intestinal barrier function

Cryptococcus neoformans and Cryptococcus gattii clinical isolates from Thailand display diverse phenotypic interactions with macrophages

Cryptococcus-macrophage interaction is crucial in the development of cryptococcocal diseases. C. neoformans and C. gattii are major pathogenic species that occupy different niches and cause different clinical manifestations. However, the differences of macrophage interaction among these species in affecting different disease outcomes and immune responses have not been clearly addressed. Here, we examined the macrophage uptake rates, intracellular loads and intracellular proliferation rates of C. neoformans and C. gattii clinical isolates from Thailand and analyzed the effect of those interactions on fungal burdens and host immune responses. C. neoformans isolates showed a higher phagocytosis rate but lower intracellular proliferation rate than C. gattii. Indeed, the high intracellular proliferation rate of C. gattii isolates did not influence the fungal burdens in lungs and brains of infected mice, whereas infection with high-uptake C. neoformans isolates resulted in significantly higher brain burdens that associated with reduced survival rate. Interestingly, alveolar macrophages of mice infected with high-uptake C. neoformans isolates showed distinct patterns of alternatively activated macrophage (M2) gene expressions with higher Arg1, Fizz1, Il13 and lower Nos2, Ifng, Il6, Tnfa, Mcp1, csf2 and Ip10 transcripts. Corresponding to this finding, infection with high-uptake C. neoformans resulted in enhanced arginase enzyme activity, elevated IL-4 and IL-13 and lowered IL-17 in the bronchoalveolar lavage. Thus, our data suggest that the macrophage interaction with C. neoformans and C. gattii may affect different disease outcomes and the high phagocytosis rates of C. neoformans influence the induction of type-2 immune responses that support fungal dissemination and disease progression. Abbreviation: Arg1: Arginase 1; BAL: Bronchoalveolar lavage; CCL17: Chemokine (C-C motif) ligand 17; CNS: Central nervous system; CSF: Cerebrospinal fluid; Csf2: Colony-stimulating factor 2; Fizz1: Found in inflammatory zone 1; HIV: Human immunodeficiency virus; ICL: Intracellular cryptococcal load; Ifng: Interferon gamma; Ip10: IFN-g-inducible protein 10; IPR: Intracellular proliferation rate; Mcp1: Monocyte chemoattractant protein 1; Nos2: Nitric oxide synthase 2; PBS: Phosphate-Buffered Saline; Th: T helper cell; Tnfa: Tumor necrosis factor alpha

NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25

Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-ᵧ production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma

ILC2s activated by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of <i>Trichinella spiralis</i> infection

<div><p>IL-25, an IL-17 family cytokine, derived from epithelial cells was shown to regulate Th2- and Th9-type immune responses. We previously reported that IL-25 was important in promoting efficient protective immunity against <i>T</i>. <i>spiralis</i> infection; however, the cellular targets of IL-25 to elicit type-2 immunity during infection have not yet been addressed. Here, we investigated IL-25-responding cells and their involvement in mediating type-2 immune response during <i>T</i>. <i>spiralis</i> infection. ILC2 and CD4⁺ Th2 cells residing in the gastrointestinal tract of <i>T</i>. <i>spiralis</i> infected mice were found to express high levels of surface interleukin-17 receptor B (IL-17RB), a component of the IL-25 receptor. Following <i>T</i>. <i>spiralis</i> infection, activated ILC2s upregulated surface MHCII expression and enhanced capacity of effector T helper cell in producing antigen-specific Th2 and Th9 cytokines through MHCII-dependent interactions. Reciprocally, lack of CD4⁺ T helper cells impaired ILC2 function to produce type 2-associated cytokines in responding to IL-25 during <i>T</i>. <i>spiralis</i> infection. Furthermore, mice deficient in IL-17RB showed markedly reduced ILC2 numbers and antigen-specific Th2 and Th9 cytokine production during <i>T</i>. <i>spiralis</i> infection. The <i>Il17rb</i>^-/- mice failed to mount effective antigen specific Th2 and Th9 functions resulting in diminished goblet cell and mast cell responses, leading to delayed worm expulsion in the intestines and muscles. Thus, our data indicated that ILC2s and CD4⁺ Th2 cells are the predominant cellular targets of IL-25 following <i>T</i>. <i>spiralis</i> infection and their collaborative interactions may play a key role in mounting effective antigen-specific Th2 and Th9 cytokine responses against <i>T</i>. <i>spiralis</i> infection.</p></div