Regulation of SETD2 maintains immune regulatory function in macrophages to suppress airway allergy.

SET domain-containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs.

Environmental pollutant 3-methyl-4-nitrophenol promotes the expression of oncostatin M to exacerbate airway allergic inflammation.

Asthma exacerbation is a common clinical occurrence. The causal factors are not fully understood yet. Environmental pollution is linked to asthma exacerbation. The objective of this study is to elucidate the role of 3-methyl-4-nitrophenol (MNP), an environmental pollutant, in asthma exacerbation. In this study, an airway allergy mouse model was established with ovalbumin as a specific antigen with or without the presence of MNP. The results showed that, in a mouse model, the intensity of airway allergy was significantly increased by exposure to MNP. RNAseq results showed an increase in endoplasmic reticulum (ER) stress-associated molecules and the Osm expression in airway epithelial cells of mice with airway allergy. Exposure of epithelial cells to MNP in culture induced the expression of oncostatin M (OSM) and ER stress associated molecules. The OSM receptor was expressed by macrophages. OSM could drive macrophages to produce tumor necrosis factor-α (TNF-α). Inhibition of PERK, one of the key molecules of ER stress, or depletion of OSM receptor in macrophages, could effectively attenuate the MNP/ovalbumin protocol induced airway allergy. To sum up, by promoting ER stress, environmental pollutant MNP can cause airway epithelial cells to produce OSM. The latter induces macrophages to produce TNF-α, which can exacerbate airway allergy.

Allergen specific immunotherapy regulates macrophage property in the airways.

BACKGROUND: Allergen specific immunotherapy (AIT) has been widely used in allergy clinics. The therapeutic effects of it are to be improved. Macrophages occupy the largest proportion of airway immune cells. The aim of this study is to measure the effects of nasal instillation AIT (nAIT) on airway allergy by regulating macrophage functions. METHODS: An airway allergy mouse model was established with the ovalbumin-alum protocol. nAIT was conducted for mice with airway allergy through nasal instillation. The effects of nAIT were compared with subcutaneous injection AIT (SCIT) and sublingual AIT (SLIT). RESULTS: Mice with airway allergy showed the airway allergic response, including lung inflammation, airway hyper responsiveness, serum specific IgE, increase in the amounts of eosinophil peroxidase, mouse mast cell protease-1, and Th2 cytokines in bronchoalveolar lavage fluid. nAIT had a much better therapeutic effect on the airway allergic response than SCIT and SLIT. Mechanistically, we observed better absorption of allergen in macrophages, better production of IL-10 by macrophages, and better immune suppressive functions in macrophages in mice received nAIT than SCIT and SLIT. CONCLUSIONS: The nAIT has a much better therapeutic effect on suppressing the airway allergic response, in which macrophages play a critical role.

Targeting the RhoA-GEF-H1 pathway of mast cells attenuates experimental airway allergy.

Mast cells are the major effector cells in allergic diseases. RhoA and its downstream pathway is associated with the pathogenesis of airway allergy. The objective of this study is to test a hypothesis that modulating the RhoA-GEF-H1 axis in mast cells can attenuate airway allergy. An airway allergic disorder (AAD) mouse model was employed. Mast cells were isolated from AAD mouse airway tissues to be analyzed by RNA sequencing. We observed that mast cells isolated from the respiratory tract of AAD mice were resistant to apoptosis. Mast cell mediator levels in nasal lavage fluid were correlated with apoptosis resistance in AAD mice. Activation of RhoA in AAD mast cells was related to resistance to apoptosis. Mast cells isolated from the airway tissues in AAD mouse exhibited strong RhoA-GEF-H1 expression. The RhoA-GEF-H1 axis was associated with the lower FasL expression in AAD mast cells. Activation of the RhoA-GEF-H1 axis promoted the production of mediators in mast cells. Inhibition of GEF-H1 facilitated the SIT-induced mast cell apoptosis and enhanced the therapeutic efficacy of AAD. In conclusion, RhoA-GEF-H1 activities are associated with resistance to apoptosis in mast cells isolated from sites of allergic lesions. The state of apoptosis resistance in mast cells is associated with the state of AAD disease. Inhibition of GEF-H1 restores the sensitivity of mast cells to apoptosis inducers, and alleviates experimental AAD in mice.

Suppression of airway allergic eosinophilia by Hp-TGM, a helminth mimic of TGF-ß.

Type 2-high asthma is a chronic inflammatory disease of the airways which is increasingly prevalent in countries where helminth parasite infections are rare, and characterized by T helper 2 (Th2)-dependent accumulation of eosinophils in the lungs. Regulatory cytokines such as TGF-ß can restrain inflammatory reactions, dampen allergic Th2 responses, and control eosinophil activation. The murine helminth parasite Heligmosomoides polygyrus releases a TGF-ß mimic (Hp-TGM) that replicates the biological and functional properties of TGF-ß despite bearing no structural similarity to the mammalian protein. Here, we investigated if Hp-TGM could alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen, house dust mite (HDM) extract or alum-adjuvanted ovalbumin protein (OVA). Intranasal administration of Hp-TGM during Alternaria exposure sharply reduced airway and lung tissue eosinophilia along with bronchoalveolar lavage fluid IL-5 and lung IL-33 cytokine levels at 24 h. The protective effect of Hp-TGM on airway eosinophilia was also obtained in the longer T-cell mediated models of HDM or OVA sensitisation with significant inhibition of eotaxin-1, IL-4 and IL-13 responses depending on the model and time-point. Hp-TGM was also protective when administered parenterally either when given at the time of allergic sensitisation or during airway allergen challenge. This project has taken the first steps in identifying the role of Hp-TGM in allergic asthma and highlighted its ability to control lung inflammation and allergic pathology. Future research will investigate the mode of action of Hp-TGM against airway allergic eosinophilia, and further explore its potential to be developed as a biotherapeutic in allergic asthma.

Rapid recruitment of CD14(+) monocytes in experimentally induced allergic rhinitis in human subjects.

BACKGROUND: Activated TH2 cells and eosinophils are hallmarks of the allergic inflammation seen in patients with allergic rhinitis (AR). However, which cells activate and attract T cells and eosinophils to the inflammatory lesion has not been determined. OBJECTIVE: We wanted to assess the role of mucosal mononuclear phagocytes, consisting of monocytes, macrophages, and dendritic cells, in the local allergic inflammatory reaction. METHODS: Patients with AR and nonatopic control subjects were challenged with pollen extract, and nasal symptoms were recorded. Mucosal biopsy specimens obtained at different time points before and after challenge were used for immunostaining in situ and flow cytometric cell sorting. Sorted mononuclear phagocytes were subjected to RNA extraction and gene expression profiling. RESULTS: In an in vivo model of AR, we found that CD14(+) monocytes were recruited to the nasal mucosa within hours after local allergen challenge, whereas conventional dendritic cells accumulated after several days of continued provocation. Transcriptomic profiling of mucosal mononuclear phagocytes sorted after 1 week of continued allergen challenge showed an activated phenotype at least partially driven by IL-4 signaling, IL-13 signaling, or both. Importantly, gene expression of several TH2-related chemokines was significantly upregulated by the mononuclear phagocyte population concomitant with an increased recruitment of CD4(+) T cells and eosinophils. CONCLUSION: Our findings suggest that the mononuclear phagocyte population is directly involved in the production of proinflammatory chemokines that attract other immune cells. Rapid recruitment of CD14(+) monocytes to the challenged site indicates that these proinflammatory mononuclear phagocytes have a central role in orchestrating local allergic inflammation.

[Diagnostic accuracy of specific IgE antibodies measurements in occupational airway allergy to high molecular weight agents]. / Trafnosc diagnostyczna oznaczen alergenowo swoistych przeciwcial IgE w zawodowej alergii dróg oddechowych na czynniki o duzej masie czasteczkowej.

BACKGROUND: The performance of specific inhalation challenge test (SICT) - reference method in diagnostics of occupational allergy - has some limitations due to health status of a particular patient. Therefore, it is extremely important to identify usefulness of other tests, and the evaluation of diagnostic accuracy of commercially available serum specific immunoglobulin E (sIgE) kits to the most common high molecular weight agents has been launched. MATERIAL AND METHODS: The study group comprised 141 subjects - 110 bakers and 31 farmers - with suspicion of occupational airway allergy. All patients underwent evaluation of serum sIgE to occupational allergens with the use of Phadia and Allergopharma kits: in bakers to flour mix and α-amylase, in farmers to epithelium of cow, pig and feathers. Specific inhalation challenge test with workplace allergens performed in all subjects was a reference method for further analysis. RESULTS: Serum specific IgE to flour mix had the highest sensitivity (Phadia - 95.6%, Allergopharma - 88.3%), while its specificity was relatively low (Phadia - 47.8%, Allergopharma - 25%). There were numerous discrepancies between the results of sIgE estimation for particular single allergens (k87, e4, e83), as well as for their mixtures (fx901, fx20, ex71), performed with the kits of both companies (Phadia vs. Allergopharma). CONCLUSIONS: Evaluation of serum specific IgE is characterized by inadequate sensitivity, specificity and predictive value to take the place of specific inhalation challenge test in diagnostics of occupational respiratory allergy. Med Pr 2017;68(1):31-43.

Antigen presenting cell-derived IL-6 restricts Th2-cell differentiation.

The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.

A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) controls allergic TH2 inflammatory responses through induction of distinct activation programs in dendritic cells (DCs). However, knowledge about TSLP receptor expression and functional consequences of receptor activation by DCs residing in the human respiratory tract is limited. OBJECTIVE: We wanted to identify TSLP-responding DC populations in the human upper airway mucosa and assess the TSLP-mediated effects on such DCs in allergic airway responses. RESULTS: We found that the TSLP receptor was constitutively and preferentially expressed by myeloid CD1c(+) DCs in the human airway mucosa and that the density of this DC subset in nasal mucosa increased significantly after in vivo allergen challenge of patients with allergic rhinitis. In vitro, TSLP strongly enhanced the capacity of CD1c(+) DCs to activate allergen-specific memory CD4(+) T cells. Moreover, TSLP rapidly induced CCR7 expression on CD1c(+) DCs. However, TH2 cytokines attenuated TSLP-mediated CCR7 induction, thus inhibiting the TSLP-induced DC migration potential to the draining lymph nodes. CONCLUSION: Our results suggest that TSLP-mediated activation of human nasal mucosal CD1c(+) DCs triggers CCR7-dependent migration to the draining lymph nodes and enhances their capacity to initiate TH2 responses. However, the observation that TH2 cytokines abrogate the induction of CCR7 implies that during a TH2-mediated inflammatory reaction, TLSP-activated CD1c(+) DCs are retained in the inflamed tissue to further exacerbate local inflammation by activating local antigen-specific memory TH2 cells.

Chimeric Antigen-LgDNA Nanoparticles Attenuate Airway Th2 Polarization.

Introduction: The therapeutic efficacy for airway allergies needs to be improved. Th2 polarization is a primary pathological feature of airway allergies. We constructed chimeric antigen-LgDNA (Lactobacillus rhamnosus DNA) nanoparticles (CAP-NPs). The effects of CAP-NPs on reconciling airway Th2 polarization were tested. Methods: In this study, disulfide bond-linked antigen-major histocompatibility complex II (MHC II)-LgDNA nanoparticles (NPs) were constructed and designated CAP-NPs. An airway Th2 polarization mouse model was established to test the effects of CAP-NPs on suppressing the Th2 response. Results: The CAP-NP components of ovalbumin (OVA), major histocompatibility complex II (MHC II), and LgDNA were confirmed in a series of laboratory tests. The CAP-NPs remained stable at pH7.2 for at least 96 h. In in vitro experiments, CAP-NPs bound to the surface of OVA-specific CD4+ T cells, which resulted in apoptosis of the antigen-specific CD4+ T cells. Removal of any of the three components from the NPs abolished the induction of apoptosis of antigen specific CD4+ T cells. CAP-NPs increased the expression of lysine-specific demethylase 5A (KDM5A) in CD4+ T cells. Histone H3K9 and the gene promoter of caspase 8 were demethylated by KDM5A, which led to transcription and expression of the caspase 8 gene. Administration of CAP-NPs significantly alleviated experimental airway Th2 polarization through activating the caspase 8-apoptosis signaling pathway. Discussion: In this paper, we constructed CAP-NPs that could induce antigen-specific CD4+ T cell apoptosis. Administration of CAP-NPs efficiently alleviated experimental airway Th2 polarization.

Direct exposure to CpG and specific antigens mitigate airway allergy through modulating dendritic cell properties.

BACKGROUND: CpG oligodeoxynucleotide (CpG-ODN; CpG, in short) has been employed as an adjuvant in allergen specific immunotherapy (AIT) to treat allergic diseases. The underlying mechanism needs to be further explained. The aim of this study is to examine the mechanism by which CpG and dust mite extracts (DME, a specific antigen) alleviate experimental airway allergy. METHODS: DME was used as the specific allergen to establish an airway allergy mouse model. The mice were directly exposed to DME and CpG through nasal instillations (the CpG.DME therapy). The response of DCs and allergic responses in the airways were assessed using immunological approaches. RESULTS: The airway allergy reaction was effectively suppressed by CpG.DME therapy. The administration of CpG or DME alone did not have any significant suppressive effects on the airway allergic response. Direct exposure to CpG.DME induced type 1 DCs (DC1s) and plasmacytoid DCs (pDCs), while CpG alone induced DC1s and DME alone induced DC2s in the airway tissues. Both DC1s and pDCs were required for the induction of type 1 regulatory T cells in the airway tissues by CpG.DME therapy. Depletion of either pDCs or DC1s abolished the induction of Tr1 cells, and abolished the suppressive effects on airway allergic response by the CpG.DME therapy. CONCLUSIONS: Direct exposure to CpG.DME induces DC1s and pDCs in the airway tissues. DC1s in synergy with pDCs induce type 1 regulatory T cells. The CpG.DME therapy is effective in suppressing allergic responses in mice with airway allergy.

Short cigarette smoke exposure facilitates sensitisation and asthma development in mice.

Epidemiological studies indicate that cigarette smoke exposure is a risk factor for increased sensitisation and asthma development. The aim of this study was to examine the impact of cigarette smoke on sensitisation and allergic airway inflammation in response to a low dose of house dust mite (HDM), and to obtain potential mechanistic insights. Mice were exposed to low doses of HDM extract combined with air or cigarette smoke exposure, either during allergen sensitisation or during the development of allergic airway disease. Mice concomitantly exposed to low-dose HDM, combined with cigarette smoke for 3 weeks, demonstrated an asthmatic phenotype with significantly increased airway eosinophilia, goblet cell metaplasia, airway hyperresponsiveness and a rise in HDM-specific serum immunoglobulin G1, compared to sole HDM or cigarette smoke exposure. In addition, short cigarette smoke inhalation, during the initial contact with HDM allergens, was sufficient to facilitate sensitisation and development of a complete asthmatic phenotype after rechallenge with HDM. Mechanistically, short cigarette smoke exposure amplified dendritic cell-mediated transport of fluorescein isothiocyanate-labelled HDM allergens to the intrathoracic lymph nodes and generated a local T-helper cell type 2 response. Short cigarette smoke exposure is sufficient to facilitate allergic sensitisation and the development of low-dose HDM-induced allergic asthma, possibly by affecting dendritic cell function.

The innate immune brakes of the lung.

Respiratory mucosal surfaces are continuously exposed to not only innocuous non-self antigens but also pathogen-associated molecular patterns (PAMPs) originating from environmental or symbiotic microbes. According to either "self/non-self" or "danger" models, this should systematically result in homeostasis breakdown and the development of immune responses directed to inhaled harmless antigens, such as T helper type (Th)2-mediated asthmatic reactions, which is fortunately not the case in most people. This discrepancy implies the existence, in the lung, of regulatory mechanisms that tightly control immune homeostasis. Although such mechanisms have been poorly investigated in comparison to the ones that trigger immune responses, a better understanding of them could be useful in the development of new therapeutic strategies against lung diseases (e.g., asthma). Here, we review current knowledge on innate immune cells that prevent the development of aberrant immune responses in the lung, thereby contributing to mucosal homeostasis.

Phosphatidylserine promotes immunotherapy for airway allergy.

Type 1 regulatory T cells (Tr1 cells) play an important role in the maintenance of the immune homeostasis in the body. The induction of Tr1 cell is to be further investigated. The interaction of phosphatidylserine (PS) with TIM3 has immune regulation functions. The objective of this study is to elucidate the role of PS-TIM3 signals in inducing Tr1 cells. In this study, mice were treated using PS or specific immunotherapy by nasal instillation. A murine model of allergic rhinitis was developed using ovalbumin as a specific antigen. We found that PS-containing nasal instillation induced Tr1 cells in the airway tissues. PS promoted gene activities associated with IL-10 through activation of TIM3 in CD4+ T cells. TIM3 mediated the effects of PS on inducing Tr1 cells, in which the TIM3- PI3K-AKT pathway played a critical role. PS boosted allergen-specific immunotherapy by inducing specific antigen Tr1 cell generation. Concomitant administration of PS and SIT resulted in better therapeutic effects on AR. In conclusion, the data demonstrate that PS can promote the specific immunotherapy for AR through inducing antigen specific Tr1 cells in the airway tissues.

Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

Substance P promotes immunotherapy efficacy for airway allergy.

Background: Allergen-specific immunotherapy (AIT) has been employed in the treatment of allergic diseases for many years. However, the effectiveness of AIT requires improvement. Substance P (SP) can interact with immune cells, modulate immune cell activity, and regulate immune reaction. The purpose of this study is to use SP as an immune regulator to enhance the therapeutic efficacy of AIT. Methods: An established mouse model of the airway allergy disorder (AAD) was employed with ovalbumin as a specific antigen. The AAD response was evaluated through established procedures. AAD mice were treated with AIT employing SP as an immune regulator. Dendritic cells were isolated from the airway tissues by magnetic cell sorting, and were analyzed by RNA sequencing (RNAseq). Results: We observed that after sensitization with ovalbumin, mice exhibited AAD-like symptoms, serum specific IgE, and Th2 polarization. The presence of SP in the course of sensitization prevented the development of AAD. Treating mice with SP by nasal instillations induced IL-10, but not TGF-ß, in dendritic cells of the airway tissues. The most differentially expressed genes (DEG) in the dendritic cells were those related to the IL-10 expression, including Il10, Tac1r, and Mtor. The gene ontology analysis showed that these DEGs mainly mapped to the tachykinin-PI3K-AKT-mTOR pathway. The addition of SP substantially enhanced the therapeutic efficacy of AIT for AAD by inducing antigen specific type 1 regulatory T cells (Tr1 cells). Conclusion: Acting as an immune regulator, SP promotes the therapeutic efficacy for AAD by inducing antigen specific Tr1 cells in the airway tissues.

Bridging micro/nano-platform and airway allergy intervention.

Allergic airway diseases, with incidence augmenting visibly as industrial development and environmental degradation, are characterized by sneezing, itching, wheezing, chest tightness, airway obstruction, and hyperresponsiveness. Current medical modalities attempt to combat these symptoms mostly by small molecule chemotherapeutants, such as corticosteroids, antihistamines, etc., via intranasal approach which is one of the most noninvasive, rapid-absorbed, and patient-friendly routes. Nevertheless, inherent defects for irritation to respiratory mucosa, drug inactivation and degradation, and rapid drug dispersal to off-target sites are inevitable. Lately, intratracheal micro/nano therapeutic systems are emerging as innovative alternatives for airway allergy interventions. This overview introduces several potential application directions of mic/nano-platform in the treatment of airway allergic diseases, including carriers, therapeutic agents, and immunomodulators. The improvement of the existing drug therapy of respiratory allergy management by micro/nano-platform is described in detail. The challenges of the micro/nano-platform nasal approach in the treatment of airway allergy are summarized and the development of micro/nano-platform is also prospected. Although still a burgeoning area, micro/nano therapeutic systems are gradually turning to be realistic orientations as crucial future alternative therapeutic options in allergic airway inflammation interventions.

XBP1 is required in Th2 polarization induction in airway allergy.

Rationale: Th2 polarization plays a central role in the pathogenesis of allergic diseases such as airway allergy. The underlying mechanism is not fully understood yet. X-box-binding protein-1 (XBP1) can regulate immune cell activities upon exposing stressful events. The role of XBP1 in the development of Th2 polarization has not yet been explored. Methods: Mice carrying Xbp1-deficient CD4+ T cells were employed to observe the role of XBP1 in the induction of airway allergy. A cell culture model was established to evaluate the role of XBP1 in facilitating the Th2 lineage commitment. Results: We found that Xbp1 ablation in CD4+ T cells prevented induction of Th2 polarization in the mouse airway tract. XBP1 was indispensable in the Th2 lineage commitment. XBP1 mediated the effects of 3-methyl-4-nitrophenol (MNP) on facilitating inducing antigen-specific Th2 response in the airways. Exposure to MNP induced expression of XBP1 in CD4+ T cells. RhoA facilitated the binding between XBP1 and GATA3 in CD4+ T cells. XBP1 induced GATA3 phosphorylation to promote the Il4 gene transcription. Modulation of the RhoA/XBP1 axis mitigated experimental allergic response in the mouse airways. Conclusions: A potential therapeutic target, XBP1, was identified in this study. XBP1 was required in the development of skewed Th2 response in the airways. Inhibiting XBP1 alleviated Th2 polarization-related immune inflammation in the airways. The data suggest that inhibiting XBP1 has the translation potential for the treatment of airway allergy.

Integrin αvß6 cooperates with resiquimod to restore antigen-specific immune tolerance in airway allergy.

BACKGROUND: Integrin αvß6 can convert the transforming growth factor (TGF)-ß precursor to the mature form. Resiquimod (R848) can generate TGF-ß-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD). METHODS: A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways. RESULTS: Exposure to R848 failed to induce Tregs in the ß6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvß6 levels in CD4+ T cells, the αvß6 then converted the TGF-ß precursor to its mature form, and thus, induced Treg generation. Administration of Rexo restored the antigen-specific immune tolerance in the airways manifesting efficiently suppressing experimental AAD by inducing antigen-specific Tregs in the airways and inhibiting antigen-specific Th2 response. CONCLUSIONS: Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD.