Therapeutic Target For Allergic Asthma Research Articles

Structure-based design and disulfide stapling of interfacial cyclic peptidic inhibitors from thymic stromal lymphopoietin (TSLP) receptor to competitively target TSLP

Human thymic stromal lymphopoietin (TSLP) is a pro-inflammatory cytokine located at the top of inflammatory cascade that makes it a promising therapeutic target in allergic asthma. The cell surface receptor of TSLP is a heterodimer consisting of a TSLP receptor (TSLPR) and an interleukin-17 receptor α (IL-7Rα). The TSLPR subunit should be first added to the free TSLP to form a TSLPR/TSLP pre-complex, which further recruits the IL-7Rα subunit to obtain the final TSLPR/IL-7Rα/TSLP complex. Previous works have been focused on targeting the IL-7Rα-binding site of TSLP. Instead, we herein reported an attempt for rational design of cyclic peptidic inhibitors to competitively disrupt the TSLPR–TSLP interaction based on their complex crystal structure by integrating dynamics simulation and energetics analysis as well as experimental assays at molecular level. An interfacial peptide segment derived from the hotspots of TSLPR that cover a specific TSLP-binding site on the TSLPR interface, which is expected to natively form a U-shaped conformation recognized by TSLP and thus compete with the cognate TSLPR for TSLP. The eS4P peptide was further stapled by a disulfide bridge between different residue pairs across its two arms, thus separately resulting in its two stapled cyclic counterparts, i.e. eS4P[189–198] and eS4P[188–200] peptides. Circular dichroism characterized that the stapling can effectively constrain the peptide into a native-like U-shpared conformation in free state, thus largely minimizing the entropy penalty upon its binding to TSLP. Affinity assays revealed that the stapling can considerably improve the peptide binding potency to TSLP by 2.9-fold and 8.3-fold at molecular level. In addition, we further demonstrated that the potent eS4P[188–200] peptide has a good selectivity for its cognate TSLP over other four noncognate cytokines IL-2, IL-7, IL-13 and IL-22 that are relevant with the TSLP. In this respect, it is considered that the disulfide-stapled cyclic peptide-mediated blockade of TLSP inflammatory cascade may be a new and promising therapeutic strategy against allergic asthma.

Group III secreted phospholipase A2 -driven lysophospholipid pathway protects against allergic asthma.

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2 s (PLA2 s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA2 (sPLA2 -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2 -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 (LPA2 ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2 -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2 -III-LPA pathway may be a new therapeutic target for allergic asthma.

Lack of Ecto-5'-Nucleotidase Protects Sensitized Mice against Allergen Challenge.

Ecto-5′-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, in mice. Here, we evaluated the response to aerosolized allergen of female-sensitized mice lacking CD73 in comparison with their wild type counterpart. Results obtained show, in mice lacking CD73, the absence of airway hyperreactivity in response to an allergen challenge, paralleled by reduced airway CD23+B cells and IL4+T cells pulmonary accumulation together with reduced mast cells accumulation and degranulation. Our findings indicate CD73 as a potential therapeutic target for allergic asthma.

Therapeutic Effects of an Anti-sialyl Lewis X Antibody in a Murine Model of Allergic Asthma.

Asthma is an allergic disease that causes severe infiltration of leukocytes into the lungs. Leukocyte infiltration is mediated by the binding of sialyl Lewis X (sLex) glycans present on the leukocytes to E-and P-selectins present on the endothelial cells at the sites of inflammation. Here, we found that mouse eosinophils express sLex glycans, and their infiltration into the lungs and proliferation in the bone marrow were significantly suppressed by an anti-sLex monoclonal antibody (mAb) F2 in a murine model of ovalbumin-induced asthma. The percentage of eosinophils in the bronchoalveolar lavage fluid and bone marrow and serum IgE levels decreased significantly in the F2-administered mice. Levels of T helper type 2 (Th2) cytokines and chemokines, involved in IgE class switching and eosinophil proliferation and recruitment, were also decreased in the F2-administered mice. An ex vivo cell rolling assay revealed that sLex glycans mediate the rolling of mouse eosinophils on P-selectin-expressing cells. These results indicate that the mAb F2 exerts therapeutic effects in a murine model of allergen-induced asthma, suggesting that sLex carbohydrate antigen could serve as a novel therapeutic target for allergic asthma.

Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor-RhoA Axis in Asthma.

We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFβ1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFβ1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR–RhoA in regulating TGFβ1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.

Promoter region single nucleotide polymorphism of siglec-8 gene associates with susceptibility to allergic asthma.

Aim: Siglec-8 is exclusively expressed on mast cells, eosinophils and basophils. Possible association of six siglec-8 single nucleotide polymorphisms (SNPs) with susceptibility to allergic asthma in the Azeri population of Iran was investigated in this study. Materials & methods: A total of 194 patients and 190 normal subjects were enrolled. PCR single strand conformation polymorphism (PCR-SSCP) was used to determine the genotypes of the studied SNPs. Results: The rs36498 showed significant association with allergic asthma (odds ratio [OR]: 0.65; p=0.022) and the T allele was found as a protective allele (OR: 0.61; p=0.008). Also, eosinophil count in the CC genotype was significantly higher than that in the other genotypes (p=0.026). Conclusion: The rs36498 is thought to influence the expression level of siglec-8. Siglec-8 could be a potential therapeutic target for allergic asthma.

Cyclic GMP-AMP Triggers Asthma in an IL-33-Dependent Manner That Is Blocked by Amlexanox, a TBK1 Inhibitor.

Extracellular host-derived DNA, as one of damage associated molecular patterns (DAMPs), is associated with allergic type 2 immune responses. Immune recognition of such DNA generates the second messenger cyclic GMP-AMP (cGAMP) and induces type-2 immune responses; however, its role in allergic diseases, such as asthma, has not been fully elucidated. This study aimed to determine whether cGAMP could induce asthma when used as an adjuvant. We intranasally sensitized mice with cGAMP together with house dust mite antigen (HDM), followed by airway challenge with HDM. We then assessed the levels of eosinophils in the broncho-alveolar lavage fluid (BALF) and serum HDM-specific antibodies. cGAMP promoted HDM specific allergic asthma, characterized by significantly increased HDM specific IgG1 and total IgE in the serum and infiltration of eosinophils in the BALF. cGAMP stimulated lung fibroblast cells to produce IL-33 in vitro, and mice deficient for IL-33 or IL-33 receptor (ST2) failed to develop asthma enhancement by cGAMP. Not only Il-33−/− mice, but also Sting−/−, Tbk1−/−, and Irf3−/−Irf7−/− mice which lack the cGAMP-mediated innate immune activation failed to increase eosinophils in the BALF than that from wild type mice. Consistently, intranasal and oral administration of amlexanox, a TBK1 inhibitor, decreased cGAMP-induced lung allergic inflammation. Thus, cGAMP functions as a type 2 adjuvant in the lung and can promote allergic asthma in manners that dependent on the intracellular STING/TBK1/IRF3/7 signaling pathway and the resultant intercellular signaling pathway via IL-33 and ST2 might be a novel therapeutic target for allergic asthma.

Blockage of sphingosine-1-phosphate receptor 2 attenuates allergic asthma in mice.

Sphingosine-1-phosphate 2 (S1P2 ) receptors have been implicated in degranulation of mast cells. However, functions of S1P2 receptors have not been investigated in an in vivo model of allergic asthma. Using an ovalbumin (OVA)-induced asthma model, the function of S1P2 receptors was evaluated in S1P2 -deficient mice or in mice treated with JTE-013, a selective S1P2 antagonist. Bone marrow-derived dendritic cells (BMDCs) were used to investigate the roles of S1P2 receptors in dendritic cell maturation and migration. Eosinophil accumulation and elevated Th2 cytokine levels in bronchoalveolar lavage fluid and inflamed lung tissues were strongly inhibited by administration of JTE-013 before OVA sensitization, before OVA challenge, and before both events. In S1P2 -deficient mice, allergic responses were significantly lower than in wild-type mice. LPS- and OVA-induced maturation of BMDCs was significantly blunted in dendritic cells from S1P2 -deficient mice and by treatment with JTE-013. Migrations of immature and mature BMDCs were also dependent on S1P2 receptors. It was found that OVA-challenged mice into which in vitro OVA primed BMDCs from S1P2 -deficient mice were adoptively transferred, had less severe asthma responses than OVA-challenged mice into which OVA-primed BMDCs from wild-type mice were adoptively transferred. Pro-allergic functions of S1P2 receptors were elucidated in a murine asthma model. S1P2 receptors were involved not only in maturation and migration of dendritic cells in the sensitization phase but also in mast cell degranulation in the challenge phase. These results suggest S1P2 receptor as a therapeutic target for allergic asthma.

The regulatory role of semaphorin 3E in allergic asthma.

Semaphorins were originally discovered as essential mediators involved in regulation of axonal growth during development of the nervous system. Ubiquitously expressed on various organs, they control several cellular functions by regulating essential signaling pathways. Among them, semaphorin3E binds plexinD1 as the primary receptor and mediates regulatory effects on cell migration, proliferation, and angiogenesis considered major physiological and pathological features in health and disease. Recent in vitro and in vivo experimental evidence demonstrate a key regulator role of semaphorin3E on airway inflammation, hyperresponsivenss and remodeling in allergic asthma. Herein, we aim to provide a broad overview of the biology of semaphorin family and review the recently discovered regulatory role of semaphorin3E in modulating immune cells and structural cells function in the airways. These findings support the concept of semaphorin3E/plexinD1 axis as a therapeutic target in allergic asthma.

Targeting the ICOS/ICOS‐L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease

BackgroundAllergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B‐cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells, are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T‐cell priming; therefore, disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells have not been evaluated.MethodsTo establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS Ligand‐targeted antibodies, three times a week for the last 2 weeks.Results TFH were first observed in the lung‐draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T‐cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness.Conclusions TFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.

The loss of DGK protects against allergic airway inflammation and airway hyperresponsiveness

Abstract Asthma is a chronic allergic inflammatory airway disease that is caused by aberrant immune responses to inhaled allergens, which leads to airflow obstruction driven in part by increased sensitivity of airway smooth muscle to contractile agonists, a process known as airway hyperresponsiveness (AHR). The inflammation of allergic asthma is driven by type 2 cytokines released by Th2 CD4+ T cells and group 2 innate lymphoid cells (ILC2) in the lung. Here, we report that targeting DAG kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protects against allergic asthma. DGKζ knockout (KO) mice exhibited reduced type 2 airway inflammation and were completely resistant to AHR induction in a mouse model of allergic asthma. Surprisingly, the mechanism by which DGKζ protected against airway inflammation and AHR were separable. Targeted deletion of DGKζ in T cells led to decreased type 2 inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to decreased AHR despite no changes in airway inflammation. Importantly, the pharmacological inhibition of DGK provided protection against airway inflammation and AHR in mice, and also reduced bronchoconstriction of human airways. Together, our data suggest that DGKζ is potentially a novel therapeutic target for allergic asthma. Moreover, the targeted deletion of DGKζ reveals that the inflammatory and AHR components of allergic asthma are not as interdependent, as generally believed.

Activated Leukocyte Cell Adhesion Molecule Stimulates the T-Cell Response in Allergic Asthma.

The activated leukocyte cell adhesion molecule (ALCAM) is a cluster of differentiation 6 ligand that is important for stabilizing the immunological synapse and inducing T-cell activation and proliferation. In this study, we investigated the role of ALCAM in the development of inflammation in allergic asthma. An ovalbumin (OVA)-induced allergic asthma model was established in wild-type (WT) and ALCAM-deficient (ALCAM-/-) mice. T-cell proliferation was evaluated in cocultures with dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) from WT and ALCAM-/- mice were cultured and adoptively transferred to OT-II mice for either OVA sensitization or challenge. An anti-ALCAM antibody was administered to assess its therapeutic potential. ALCAM concentrations in the sputum and serum of children with asthma were quantified by ELISA. Inflammatory responses were lower in ALCAM-/- mice than in WT mice, and T cells cocultured with DCs from ALCAM-/- mice showed reduced proliferation relative to those cocultured with DCs from WT mice. A decreased inflammatory response was observed upon adoptive transfer of BMDCs from ALCAM-/- mice as compared with that observed after transfer of BMDCs from WT mice. In addition, anti-ALCAM antibody-treated mice showed a reduced inflammatory response, and sputum and serum ALCAM concentrations were higher in children with asthma than in control subjects. ALCAM contributes to OVA-induced allergic asthma by stimulating T-cell activation and proliferation, suggesting it as a potential therapeutic target for allergic asthma.

Functions of the ‘alarmin’ cytokine IL-25 in house dust mites-induced allergic asthma-like chronic pulmonary inflammation

Abstract Allergic inflammatory lung disease is a complex immune response orchestrated by many cytokines, chemokines and other factors signaling danger. One of these is the alarmin IL-25, an epithelial cell-derived cytokine secreted at mucosal sites in response to various allergens. Although IL-25 is a member of the IL-17 cytokine family and it is the only member to promote type-2 responses. IL-25 activities overlap with those of IL-33 and TSLP, two other cytokines secreted by mucosal epithelial cells; all three activate innate lymphoid cells type 2 (ILC2s). We set out to elucidate unique/significant roles of IL-25 in the chronic asthma-like lung inflammation model induced by repeated exposures to house dust mites. If unique/significant contributions could be identified in this physiologically relevant model, IL-25 could be a potential therapeutic target in allergic asthma. To carry out these studies we generated mice with global or conditional deletion of IL-17RB and CIKS (a.k.a. Act-1, Traf3ip2). Surprisingly we found that blocking IL-25 signaling in lung CD11c+ cells reduced expression of IL-9 and IL-13, cytokines that are critical in asthma and that derive primarily from Th9 and Th2 cells, respectively, during the chronic stages. IL-25 signaling in CD11c+ cells also contributed significantly to mast cell accumulation and ultimately lung remodeling. We will present investigations of potential mechanisms underlying the effects of IL-25 signaling in CD11c+ lung cells. Our data demonstrate that IL-25 signaling in CD11c+ cells makes physiologically important contributions in the chronic HDM-induced model of allergic asthma, findings that should encourage future studies of this cytokine as a therapeutic target.

MiR-155 contributes to Df1-induced asthma by increasing the proliferative response of Th cells via CTLA-4 downregulation

Allergen-induced airway inflammation is characterized by Th2-mediated eosinophilic inflammation in the lungs. While the molecular mechanisms leading to this abnormal Th2 response remain unclear. Recent studies have demonstrated that MicroRNAs (miRNAs) modulate allergic airway inflammation. In this study, the role of miRNAs in allergic asthma pathogenesis was examined. Differentially expressed miRNAs were identified via miRNA microarray, with miR-155 being among the most highly expressed in asthma mice lungs. Examination of miR-155 overexpression resulted in enhanced inflammation and mucus hypersecretion in the lungs of allergen-challenged mice compared with control animals. Furthermore, CTLA-4, an important negative regulator of T-cell activation, was identified as a direct miR-155 target. Moreover, miR-155 overexpression in CD4+ T cells resulted in decreased CTLA-4 levels and a subsequent increased proliferative response. Collectively, these findings suggest that miR-155 might contribute to allergic asthma by increasing the proliferative response of Th cells via CTLA-4 downregulation and thus may be a potential therapeutic target for allergic asthma.

Heme Oxygenase-1-Expressing Dendritic Cells Promote Foxp3+ Regulatory T Cell Differentiation and Induce Less Severe Airway Inflammation in Murine Models.

Dendritic cells (DCs) are critical for instructing immune responses toward inflammatory or anti-inflammatory status. Heme oxygenase-1 (HO-1) is known for its cytoprotective effect against oxidative stress and inflammation, suggesting its immune regulatory role in allergic lung inflammation. HO-1 has been implicated in affecting DC maturation; however, its role in DC-mediated T-cell differentiation is unclear. In this study, we demonstrated that HO-1-expressing bone marrow-derived dendritic cells (BM-DCs) displayed tolerogenic phenotypes, including their resistance to lipopolysaccharide (LPS)-induced maturation, high level expression of IL-10, and low T-cell stimulatory activity. In addition, HO-1-expressing DCs were able to induce antigen-specific Foxp3+ regulatory T cells (Treg) differentiation in vitro and in vivo. Also, HO-1-expressing DCs modulated the severity of lung inflammatory responses in two murine models of airway inflammation. This study provided evidence supporting the role of HO-1-expressing DCs in tolerance induction and as a potential therapeutic target for allergic asthma as well as other inflammatory diseases.

Heme oxygenase-1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2-mediated allergic airway inflammation.

The anti-inflammatory role of heme oxygenase-1 (HO-1) has been studied extensively in many disease models including asthma. Many cell types are anti-inflammatory targets of HO-1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO-1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen-induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up-regulation of HO-1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC-II and activation marker CD200R on basophils, blocked DQ-ovalbumin uptake and promoted basophil apoptosis both invitro and invivo, leading to the inhibition of T helper type 2 polarization. These effects of HO-1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO-1. Furthermore, adoptive transfer of HO-1-modified basophils reduced ovalbumin-induced allergic airway inflammation. The above effects of HO-1 can be reversed by the HO-1 inhibitor Sn-protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO-1 may involve multiple immune cells. Collectively, our findings demonstrated that HO-1 exerted its anti-inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.

IL-25 as a potential therapeutic target in allergic asthma.

Allergic asthma is a prevalent disease characterized by intermittent airway hyperresponsiveness resulting in airway narrowing, debilitating wheezing and shortness of breath that in severe cases can prove fatal. Notably, the number of sufferers, especially among children, has increased dramatically over recent decades and the WHO estimates that 235 million people worldwide suffer from this disorder. Asthma can be induced by a variety of provocative allergic stimuli and is associated with pulmonary inflammatory infiltrates including T helper 2 (Th2) cells and type-2 innate lymphoid cells (ILC2s) secreting the type-2 cytokines IL-4, IL-5 IL-9 and IL-13. These cytokines coordinate the inappropriate muscular contraction, immunoglobulin E production, eosinophilia and mucus hypersecretion that typify asthma. Despite being characterized for over a century, asthma is often underdiagnosed and there have been few therapeutic advances since the introduction of steroids in the 1950s (e.g., antileukotrienes and anti-IgE treatment). In part, this is due to the complexity of the disease with the existence of subtypes of asthma only now being fully realized. These recent improvements in our understanding have resulted in clinical trials establishing the potential of biological asthma treatments such as antibodies that neutralize IL-5 and IL-13. However, these therapies only work in subsets of asthma patients, leading to an unmet need for additional novel treatments. A triad of lung epithelium-derived cytokines, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), that lie upstream of the effector type-2 cytokines, have emerged as important mediators in asthma and are therefore potential treatment targets [1]. IL-25 was identified in 2001 and found to induce type-2 immune responses in human and animal studies [2]. It is a member of the IL-17 cytokine family and in contrast to IL-17A elicits type-2 cytokine production via its receptor IL17 receptor beta (IL-17RB, IL-25R) [3]. Although IL-25 is reported to be expressed by a range of structural (including bronchial epithelial cells and endothelial cells) and immune cells (Th cells, macrophages, dendritic cells, basophils and mast cells), it is generally difficult to detect IL-25 protein, presumably because it is produced in low amounts or consumed rapidly. Thus, the cellular sources of IL-25 and the mechanisms by which it is released during disease still remain unclear. A range of immune cells are responsive to IL-25, such as Th2 and Th9 cells, ILC2, monocytes, eosinophils and natural killer T cells; all of which have been shown to contribute to asthma pathogenesis. Mouse models have indicated that IL-25 may represent an important target in asthma, IL-25 as a potential therapeutic target in allergic asthma

Eosinophil Apoptosis as a Therapeutic Target in Allergic Asthma

Asthma is a chronic inflammatory disease of the airways manifesting in many different phenotypes. Allergic asthma, comprising approximately half of patients with asthma, is characterized by the accumulation of eosinophils into the lungs. Eosinophils release factors that damage the surrounding cells and participate in the maintenance and exacerbation of inflammation. In the absence of any inflammatory survival-prolonging factors, eosinophils die by apoptosis in few days but in inflamed airways, eosinophil survival is thought to be prolonged due to the surrounding pro-inflammatory factors such as IL-5, IL-3 and GM-CSF. Resolution of eosinophilic inflammation is an important goal in the treatment of allergic asthma. Apoptosis is a physiological and non-inflammatory way to eliminate these harmful cells, and development of drugs targeting eosinophil apoptosis is one possible strategy for the therapy of allergic asthma. Importance of this strategy is supported by the fact that promotion of eosinophil apoptosis is a property of many anti-asthmatic agents such as glucocorticoids, the current main anti-inflammatory therapy of asthma, theophylline and leukotriene modifiers. β2 agonists have been shown to modulate eosinophil longevity by increasing survival. Also, anti-IL-5 antibody mesolizumab has shown efficacy in reducing asthma exacerbations in patients with severe eosinophilic asthma. Many potential future anti-asthmatic agents, such as Siglec-8 activating antibody and novel humanized anti-IL-5 antibody MEDI-563, have the property of inducing eosinophil apoptosis. This MiniReview aims to present eosinophil apoptosis as a therapeutic target in the treatment of allergic asthma. We summarize the effects and mechanisms of current and potential future anti-asthmatic drugs on eosinophil apoptosis and additionally, discuss the potential factors that promote eosinophil longevity in the lungs.

Atrial natriuretic peptide/natriuretic peptide receptor A (ANP/NPRA) signaling pathway: A potential therapeutic target for allergic asthma

Allergic asthma is a chronic inflammatory disease of airway and immune disorder is an acknowledged mechanism. Numerous data demonstrate Th1/Th2 cells play an important role in the development of allergic asthma. Atrial natriuretic peptide (ANP) is a multifunctional hormone secreted by cardiac atria, lung, and so forth, which has been recognized for several decades due to its general effects on cardiovascular system, and natriuretic peptide receptor A (NPRA) is the major effecting receptor for ANP. In recent years, more and more studies suggest that ANP/NPRA signaling pathway is implicated in modulation of immnue and inflammatory reaction. Moreover, there are some reports about significant changes of ANP production in peripheral blood from asthmatics in acute exacerbation compared with patients during the remission and the healthy. Nevertheless, it is unknown that why ANP shows an observable change and what role ANP plays in asthma until now. We propose that ANP/NPRA signaling pathway is involved in immune dysfunction and airway inflammation of allergic asthma based on our experimental results, which suggests ANP/NPRA signaling pathway may be a potential therapeutic target for allergic asthma.

Airway Inflammation and IgE Production Induced by Dust Mite Allergen-Specific Memory/Effector Th2 Cell Line Can Be Effectively Attenuated by IL-35

CD4(+) memory/effector T cells play a central role in orchestrating the rapid and robust immune responses upon re-encounter with specific Ags. However, the immunologic mechanism(s) underlying these responses are still not fully understood. To investigate this, we generated an allergen (major house dust mite allergen, Blo t 5)-specific murine Th2 cell line that secreted IL-4, IL-5, IL-10, and IL-13, but not IL-9 or TNF-α, upon activation by the cognate Ag. These cells also exhibited CD44(high)CD62L(-) and CD127(+) (IL-7Rα(+)) phenotypes, which are characteristics of memory/effector T cells. Experiments involving adoptive transfer of this Th2 cell line in mice, followed by three intranasal challenges with Blo t 5, induced a dexamethasone-sensitive eosinophilic airway inflammation. This was accompanied by elevation of Th2 cytokines and CC- and CXC-motif chemokines, as well as recruitment of lymphocytes and polymorphic mononuclear cells into the lungs. Moreover, Blo t 5-specific IgE was detected 4 d after the last intranasal challenge, whereas elevation of Blo t 5-specific IgG1 was found at week two. Finally, pulmonary delivery of the pVAX-IL-35 DNA construct effectively downregulated Blo t 5-specific allergic airway inflammation, and i.m. injection of pVAX-IL-35 led to long-lasting suppression of circulating Blo t 5-specific and total IgE. This model provides a robust research tool to elucidate the immunopathogenic role of memory/effector Th2 cells in allergic airway inflammation. Our results suggested that IL-35 could be a potential therapeutic target for allergic asthma through its attenuating effects on allergen-specific CD4(+) memory/effector Th2 cell-mediated airway inflammation.