Monocyte-derived dendritic cells induce a house dust mite-specific Th2 allergic inflammation in the lung of humanized SCID mice: involvement of CCR7

In rodents, airway dendritic cells (DCs) capture inhaled Ag, undergo maturation, and migrate to the draining mediastinal lymph nodes (MLN) to initiate the Ag-specific T cell response. However, the role of human DCs in the pathogenesis of the Th2 cell-mediated disease asthma remains to be clarified. Here, by using SCID mice engrafted with T cells from either house dust mite (HDM)-allergic patients or healthy donors, we show that DCs pulsed with Der p 1, one of the major allergens of HDM, and injected intratracheally into naive animals migrated into the MLN. In the MLN, Der p 1-pulsed DCs from allergic patients induced the proliferation of IL-4-producing CD4(+) T cells, whereas those from healthy donors induced IFN-gamma-secreting cells. In reconstituted human PBMC-reconstituted SCID mice primed with pulsed DCs from allergic patients, repeated exposure to aerosols of HDM induced 1) a strong pulmonary inflammatory reaction rich in T cells and eosinophils, 2) an increase in IL-4 and IL-5 production in the lung lavage fluid, and 3) increased IgE production compared with that in mice primed with unpulsed DCs. All these effects were reduced following in vivo neutralization of the CCR7 ligand secondary lymphoid tissue chemokine. These data in human PBMC-reconstituted SCID mice show that monocyte-derived DCs might play a key role in the pathogenesis of the pulmonary allergic response by inducing Th2 effector function following migration to the MLN.     

Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma

Increased levels of NO in exhaled air in association with increased NO synthetase (NOS)2 expression in bronchial epithelial are hallmark features of asthma. It has been suggested that NO contributes to asthma pathogenesis by selective down-regulation of TH1 responses. We demonstrate, however, that NO can reversibly limit in vitro expansion of both human TH1 and TH2 CD4+ T cells. Mechanistically, NO induces cGMP-mediated reversible STAT5 dephosphorylation and therefore interferes with the IL-2R activation cascade. Human bronchial epithelial cells (HBEC) up-regulate NOS2 after stimulation with IFN-gamma secreted by TH1 CD4+ T cells and release NO, which inhibits both TH1 and TH2 cell proliferation. This reversible T cell growth arrest depends on NO because T cell proliferation is completely restored after in vitro blocking of NOS2 on HBEC. HBEC thus drive the effector end of a TH1-controlled feedback loop, which protects airway mucosal tissues at the potential lesional site in asthma from overwhelming CD4+ TH2 (and potentially TH1) responses following allergen exposure. Variations in the efficiency of this feedback loop provides a plausible mechanism to explain why only a subset of atopics sensitized to ubiquitous aeroallergens progress to expression of clinically relevant levels of airways inflammation.     

TNF receptor-associated factor 1 expressed in resident lung cells is required for the development of allergic lung inflammation

TNF is a major therapeutic target in a range of chronic inflammatory disorders, including asthma. TNFR-associated factor (TRAF)1 is an intracellular adaptor molecule important for signaling by TNFR. In this study, we investigated the role of TRAF1 in an adoptive transfer model of allergic lung inflammation. Mice deficient in TRAF1 (TRAF1(-/-)) and wild-type (WT) control animals were adoptively transferred with WT OVA-immune CD4(+) T cells, exposed to an aerosol of LPS-free OVA, and analyzed for the development of allergic lung inflammation. In contrast to WT mice, TRAF1(-/-) recipients failed to display goblet cell hyperplasia, eosinophilic inflammation, and airway hyperresponsiveness in this model of asthma. Neither T cell recruitment nor expression of the proinflammatory cytokines IL-4, IL-5, IL-13, or TNF occurred in the lungs of TRAF1(-/-) mice. Although purified myeloid TRAF1(-/-) dendritic cells (DCs) exhibited normal Ag-presenting function and transmigratory capacity in vitro and were able to induce OVA-specific immune responses in the lung draining lymph nodes (LNs) following adoptive transfer in vivo, CD11c(+)CD11b(+) DCs from airways of TRAF1(-/-) recipients were not activated, and purified draining LN cells did not proliferate in vitro. Moreover, transfer of WT or TRAF1(-/-) DCs failed to restore T cell recruitment and DC activation in the airways of TRAF1(-/-) mice, suggesting that the expression of TRAF1 in resident lung cells is required for the development of asthma. Finally, we demonstrate that T cell-transfused TRAF1(-/-) recipient mice demonstrated impaired up-regulation of ICAM-1 expression on lung cells in response to OVA exposure.     

Immunosuppression in Early Postnatal Days Induces Persistent and Allergen-Specific Immune Tolerance to Asthma in Adult Mice

Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.     

Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma

Dendritic cells (DCs) are generally held responsible for initiating and maintaining allergic T helper 2 (T(H)2)-cell responses to inhaled allergens in asthma. Although the epithelium was initially considered to function solely as a physical barrier, it is now seen as a central player in the T(H)2-cell sensitization process by influencing the function of DCs. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DCs. A better understanding of these interactions, ascertained from human and animal studies, might lead to better prevention and treatment of asthma.     

Role of Arginase 1 from Myeloid Cells in Th2-Dominated Lung Inflammation

Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution.     

Identification of histone acetylation in a murine model of allergic asthma by proteomic analysis

The pathogenesis of asthma is closely related to histone acetylation modification, but the specific acetylation sites related to this process remain indistinct. Herein, our study sought to identify differentially modified acetylation sites and their expression distribution in cells involved in asthma in lung tissues. The airway hyper-responsiveness, inflammation, and remodeling were assessed by non-invasive whole-body plethysmography, ELISA, and hematoxylin-eosin staining to confirm the successful establishment of the allergic asthma model. Afterward, the differentially modified acetylation sites in asthmatic lung tissues were identified and validated by using proteomics and western blotting, respectively. The immunohistochemistry analysis was applied to reveal the distribution of identified acetylation sites in asthmatic lung tissues. A total of 15 differentially modified acetylation sites, including 13 upregulated (H3K9ac, H3K14ac, H3K18ac, H3K23ac,H3K27ac, H3K36ac, H2B1KK120ac, H2B2BK20ac, H2BK16ac, H2BK20ac, H2BK108ac, H2BK116ac, and H2BK120ac) and 2 downregulated (H2BK5ac and H2BK11ac) sites were identified and validated. Furthermore, immunohistochemical staining of lung tissues showed that nine of the identified histone acetylation sites (H2BK5, H2BK11, H3K18, H2BK116, H2BK20, H2BK120, H3K9, H3K36, and H3K27) were differentially expressed in airway epithelial cells, and the acetylation of identified H3 histones were observed in both eosinophil and perivascular inflammatory cells. Additionally, differential expression of histone acetylation sites was also observed in nucleus of airway epithelial cells, vascular smooth muscle cells, perivascular inflammatory cells, and airway smooth muscle cells. In conclusion, we identified potential acetylation sites associated with asthma pathogenesis. These findings may contribute greatly in the search for therapeutic approaches for allergic asthma.     

Airway activation of formyl peptide receptors inhibits Th1 and Th17 cell responses via inhibition of mediator release from immune and inflammatory cells and maturation of dendritic cells

Formyl peptide receptors (FPRs) are chemoattractant receptors that mediate inflammatory cell responses to infection. Recent evidence indicates that noneosinophilic asthma phenotypes can be developed by both Th1 and Th17 cell responses when exposed to LPS-containing allergens. In this study, we evaluated the effects of airway activation of FPRs by their synthetic agonist, Trp-Lys-Tyr-Met-Val-D-Met (W-peptide), on the development of Th1 and Th17 cell responses in a noneosinophilic asthma mouse model. A noneosinophilic asthma mouse model was generated by intranasal sensitization with 10 μg of LPS plus 75 μg of OVA on days 0, 1, 2, and 7. Mice were then challenged with 50 μg of OVA alone on days 14, 15, 21, and 22. W-peptide was administered during the sensitization period, and immune and inflammatory responses were evaluated after OVA challenge. Lung inflammation after OVA challenge was partly abolished by airway activation of FPRs during sensitization. Maturation of dendritic cells (DCs) and migration of DCs from the lung to lung-draining lymph nodes were inhibited by FPR activation. In addition, airway activation of FPRs inhibited allergen-specific T cell proliferation in the lymph nodes. Production of IL-12 and IL-6 (Th1- and Th17-polarizing cytokines) from lung DCs was decreased by airway activation of FPRs. This effect resulted in the inhibition of allergen-specific Th1 and Th17 cell responses. Airway activation of FPRs during sensitization effectively prevents the development of Th1 and Th17 cell responses induced by LPS-containing allergens via multiple mechanisms, such as inhibition of DC maturation and migration and the production of Th1- and Th7-polarizing cytokines.     

Flt3 ligand preferentially increases the number of functionally active myeloid dendritic cells in the lungs of mice

In the present study, we investigated the effects of in vivo Flt3L administration on the generation, phenotype, and function of lung dendritic cells (DCs) to evaluate whether Flt3L favors the expansion and maturation of a particular DC subset. Injection of Flt3L into mice resulted in an increased number of CD11c-expressing lung DCs, preferentially in the alveolar septa. FACS analysis allowed us to quantify a 19-fold increase in the absolute numbers of CD11c-positive, CD45R/B220 negative DCs in the lungs of Flt3L-treated mice over vehicle-treated mice. Further analysis revealed a 90-fold increase in the absolute number of myeloid DCs (CD11c positive, CD45R/B220 negative, and CD11b positive) and only a 3-fold increase of lymphoid DCs (CD11c positive, CD45R/B220 negative, and CD11b negative) from the lungs of Flt3L-treated mice over vehicle-treated mice. Flt3L-treated lung DCs were more mature than vehicle-treated lung DCs as demonstrated by a significantly higher percentage of cells expressing MHC class II, CD86, and CD40. Freshly isolated Flt3L lung DCs were not fully mature, because after an overnight culture they continued to increase accessory molecule expression. Functionally, Flt3L-treated lung DCs were more efficient than vehicle-treated DCs at stimulating naive T cell proliferation. Our data show that administration of Flt3L favors the expansion of myeloid lung DCs over lymphoid DCs and enhanced their ability to stimulate naive lymphocytes.     

Flt3-ligand, IL-4, GM-CSF, and adherence-mediated isolation of murine lung dendritic cells: assessment of isolation technique on phenotype and function

Lung dendritic cells (DCs) are difficult to study due to their limited quantities and the complexities required for isolation. Although many procedures have been used to overcome this challenge, the effects of isolation techniques on lung DCs have not been reported. The current study shows that freshly isolated DCs (CD11c+) have limited ability to induce proliferation in allogeneic T cells, and are immature as indicated by low cell surface expression of costimulatory molecules compared with liver or splenic DCs. DCs isolated after overnight culture or from mice treated with Flt3L are phenotypically mature and potent stimulators of allogeneic T cells. DCs could not be propagated from lung mononuclear cells in response to IL-4 and GM-CSF. Contrary to data reported for nonpulmonary DCs, expression of CCR6 was decreased on mature lung DCs, and only a subset of mature DCs expressed higher levels of CCR7. Absence of CD8alpha expression indicates that freshly isolated DCs are myeloid-type, whereas mature DCs induced by overnight culture are both "lymphoid" (CD8alpha+) and "myeloid" (CD8alpha-). DCs from mice genetically deficient in CD8alpha expression were strong simulators of allogeneic T cells which was consistent with data showing that CD8alpha- DCs from CD8alpha-sufficient mice are better APCs compared with CD8alpha+ DCs from the same mice. These data show that freshly isolated lung DCs are phenotypically and functionally distinct, and that the isolation technique alters the biology of these cells. Therefore, lung DC phenotype and function must be interpreted relative to the technique used for isolation.     

Splenic dendritic cells induced by oral antigen administration are important for the transfer of oral tolerance in an experimental model of asthma

Peripheral tolerance can be induced after the feeding of Ag, which is referred to as oral tolerance. We demonstrated in this study that the oral administration of OVA induced tolerance in an experimental model of asthma in mice, and investigated which cells function as the regulatory cells in the transfer of this oral tolerance. In OVA-fed mice, the percentage of eosinophils in bronchoalveolar lavage fluid, serum IgE levels, airway hyperresponsiveness, and mRNA levels of IL-13 and eotaxin were significantly lower than found in nonfed mice. Histological examination of lung tissue showed a suppression of the accumulation of inflammatory cells in the peribronchial area of OVA-fed mice. Feeding after the first immunization or between the first and the second immunization suppressed these findings, whereas feeding just before the airway Ag challenge did not. The suppression of disease in OVA-fed mice was successfully transferred by injection of whole spleen cells of OVA-fed mice. When CD11c+ dendritic cells (DCs) were removed from splenocytes, this transfer of suppression was completely abolished. The injection of splenic DCs purified from OVA-fed mice alone transferred the suppression, whereas the injection of splenic DCs from naive mice that were cocultured with OVA in vitro did not. These data suggest that not only CD4+ T cells, but also CD11c+ DCs induced by Ag feeding are important for the active transfer of oral tolerance in this murine experimental model of asthma.     

Analysis of Pulmonary Dendritic Cell Maturation and Migration during Allergic Airway Inflammation

Dendritic cells (DCs) are the key players involved in initiation of adaptive immune response by activating antigen-specific T cells. DCs are present in peripheral tissues in steady state; however in response to antigen stimulation, DCs take up the antigen and rapidly migrate to the draining lymph nodes where they initiate T cell response against the antigen^1,2. Additionally, DCs also play a key role in initiating autoimmune as well as allergic immune response³.DCs play an essential role in both initiation of immune response and induction of tolerance in the setting of lung environment⁴. Lung environment is largely tolerogenic, owing to the exposure to vast array of environmental antigens⁵. However, in some individuals there is a break in tolerance, which leads to induction of allergy and asthma. In this study, we describe a strategy, which can be used to monitor airway DC maturation and migration in response to the antigen used for sensitization. The measurement of airway DC maturation and migration allows for assessment of the kinetics of immune response during airway allergic inflammation and also assists in understanding the magnitude of the subsequent immune response along with the underlying mechanisms.Our strategy is based on the use of ovalbumin as a sensitizing agent. Ovalbumin-induced allergic asthma is a widely used model to reproduce the airway eosinophilia, pulmonary inflammation and elevated IgE levels found during asthma^6,7. After sensitization, mice are challenged by intranasal delivery of FITC labeled ovalbumin, which allows for specific labeling of airway DCs which uptake ovalbumin. Next, using several DC specific markers, we can assess the maturation of these DCs and can also assess their migration to the draining lymph nodes by employing flow cytometry.     

Targeting phosphoinositide 3-kinase δ for allergic asthma

Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.     

Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma

Dendritic cells (DCs) appear to be strategically implicated in allergic diseases, including asthma. Matrix metalloproteinase (MMP)-9 mediates transmigration of inflammatory leukocytes across basement membranes. This study investigated the role of MMP-9 in airway DC trafficking during allergen-induced airway inflammation. MMP-9 gene deletion affected the trafficking of pulmonary DCs in a specific way: only the inflammatory transmigration of DCs into the airway lumen was impaired, whereas DC-mediated transport of airway Ag to the thoracic lymph nodes remained unaffected. In parallel, the local production of the Th2-attracting chemokine CC chemokine ligand 17/thymus and activation-regulated chemokine, which was highly concentrated in purified lung DCs, fell short in the airways of allergen-exposed MMP-9(-/-) mice. This was accompanied by markedly reduced peribronchial eosinophilic infiltrates and impaired allergen-specific IgE production. We conclude that the specific absence of MMP-9 activity inhibits the development of allergic airway inflammation by impairing the recruitment of DCs into the airways and the local production of DC-derived proallergic chemokines.     

IL-23/Th17轴在变应性哮喘中的研究进展

变应性哮喘是一种由辅助性T细胞（T helper cell,Th cell）调节的慢性炎症性疾病。Th1/Th2的失衡一直被认为是变应性哮喘的发病机制,Th2细胞及其分泌的细胞因子白介素4（interleukin 4,IL-4）、IL-5以及IL-13在变应性哮喘特异性症状的发病中发挥重要作用。最近研究发现Th17细胞及其分泌的IL-17参与变应性哮喘的发展过程,IL-23在Th17细胞维持生存和功能成熟中发挥重要作用,并参与抗原诱导的气道炎症反应。该文对目前IL-23/Th17轴在变应性气道炎症反应中的研究进展作一综述。     

Evidence for local dendritic cell activation in pulmonary sarcoidosis

Background

Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation.

Methods

We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c⁺DCs was assessed in mucosal airway biopsies.

Results

mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4⁺ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86⁺ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients.

Conclusion

Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.     

Inert 50-nm polystyrene nanoparticles that modify pulmonary dendritic cell function and inhibit allergic airway inflammation

Nanoparticles are being developed for diverse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c(+)MHCII(hi) DCs in the lung and draining LN and allergen-laden CD11b(hi)MHCII(hi) DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11b(hi) DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4(+) T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.     

IL-13在支气管哮喘中的作用机制及治疗靶位

支气管哮喘是由多种细胞包括气道炎性细胞、结构细胞和多种细胞组分参与的气道慢性炎症性疾病。其发病原因复杂,以反复发作的呼吸困难、气道的高反应性和慢性炎症为特点。细胞因子作为免疫活性细胞中的效应分子,具有的免疫调节作用,诸多学者认为白介素-13(interleukin-13,IL-13)在哮喘发病中扮演重要角色,其拮抗剂有望成为哮喘治疗的新方法,本文欲将IL-13的生物学功能、IL-13在支气管哮喘中的作用机制及干预治疗靶位加以综述,为制定哮喘防治策略、开发新治疗技术提供新思路。     

Elevated S100A4 in asthmatics and an allergen-induced mouse asthma model

The elevated S100A4 level has been found in some inflammatory diseases. However, the expression and role of S100A4 in asthma is unknown. The expression of S100A4 in induced sputum and plasma from healthy control and asthmatics were assessed by ELISA. Then an allergen-induced asthma mouse model treatment with anti-S100A4 antibody was used to explore the role of S100A4 in the pathogenesis of asthma. The S100A4 levels in sputum not in plasma in asthmatics were significantly increased than those of healthy controls and were negatively correlated with some lung function parameters and were positively correlated with sputum eosinophilia and lymphocyte. The expression of S100A4 in the lung as well as in BALF were also significantly higher in the asthma mouse model and treatment with anti-S100A4 antibody exhibited reductions in inflammatory cell accumulation, inflammatory mediators, and airway hyper-responsiveness. We further showed that LY294002, a specific inhibitor of PI3K, markedly decreased S100A4 expression in lung and S100A4 secretion in BALF in asthmatic mice. In conclusion, these data demonstrated that S100A4 may be involved in the pathogenesis of airway inflammation in asthma.     

Increased Th2 cytokine secretion, eosinophilic airway inflammation, and airway hyperresponsiveness in neurturin-deficient mice

Neurotrophins such as nerve growth factor and brain-derived neurotrophic factor have been described to be involved in the pathogenesis of asthma. Neurturin (NTN), another neurotrophin from the glial cell line-derived neurotrophic factor family, was shown to be produced by human immune cells: monocytes, B cells, and T cells. Furthermore, it was previously described that the secretion of inflammatory cytokines was dramatically stimulated in NTN knockout (NTN(-/-)) mice. NTN is structurally similar to TGF-β, a protective cytokine in airway inflammation. This study investigates the implication of NTN in a model of allergic airway inflammation using NTN(-/-) mice. The bronchial inflammatory response of OVA-sensitized NTN(-/-) mice was compared with wild-type mice. Airway inflammation, Th2 cytokines, and airway hyperresponsiveness (AHR) were examined. NTN(-/-) mice showed an increase of OVA-specific serum IgE and a pronounced worsening of inflammatory features. Eosinophil number and IL-4 and IL-5 concentration in the bronchoalveolar lavage fluid and lung tissue were increased. In parallel, Th2 cytokine secretion of lung draining lymph node cells was also augmented when stimulated by OVA in vitro. Furthermore, AHR was markedly enhanced in NTN(-/-) mice after sensitization and challenge when compared with wild-type mice. Administration of NTN before challenge with OVA partially rescues the phenotype of NTN(-/-) mice. These findings provide evidence for a dampening role of NTN on allergic inflammation and AHR in a murine model of asthma.