Allergen-induced Airway Inflammation Research Articles

Clearance of apoptotic cells by lung alveolar macrophages prevents development of house dust mite-induced asthmatic lung inflammation

Poor clearance of apoptotic cells has been suggested to contribute to severe asthma, but whether uptake of apoptotic cells by lung phagocytes might dampen house dust mite (HDM)-induced lung inflammation has not been shown. This study investigated whether apoptotic cell engulfment in the murine lung impacts the development of allergen-induced asthmatic airway inflammation and which immune modulating mechanisms were activated. Apoptotic cells were infused into the lungs of mice challenged with HDM allergen and lung inflammation, expression of suppressive molecules, and induction of regulatory T cells were monitored. Additionally, an adenosine receptor agonist was tested to study the mechanism of suppression elicited by apoptotic cells. Apoptotic cell uptake by lung alveolar macrophages suppressed HDM-driven allergic asthma. This was associated with promoting the regulatory T cell-inducing molecule retinoic acid, inhibiting inflammatory cytokine production, and making macrophages more susceptible to receiving suppressive signals from adenosine. Correspondingly, adenosine receptor agonist treatment also limited HDM-driven allergic airway inflammation through an action on alveolar macrophages. These data provide insight into the mechanisms by which lung macrophages dampen allergen-induced airway inflammation. They suggest that targeting lung macrophages to increase their phagocytic capacity, enhance their ability to make retinoic acid, dampen their capacity to make inflammatory cytokines, and increase their responsiveness to adenosine, could be useful to suppress allergic responses.

Effects of allergic airway inflammation and chronic intermittent hypoxia on systemic blood pressure.

Asthma and obstructive sleep apnea (OSA) are highly prevalent chronic conditions, and both are associated with systemic hypertension. Additionally, asthma and OSA reciprocally interact, mutually exacerbating each other. In this study, we tested the effect of allergen-induced lower airway inflammation and concurrent chronic intermittent hypoxia (CIH) on systemic blood pressure (BP), pulmonary function, and proinflammatory cytokines, in a rat model. Brown Norway rats were exposed to 43 days of normoxia (NORM) or CIH, concurrent with weekly house dust mite (HDM) challenges. BP was measured 1 day after the last HDM challenge. On day 44, pulmonary function was tested, and blood for Th-2 and Th-1 cytokine levels was collected. HDM significantly increased mean (P = 0.002), systolic (P = 0.003), and diastolic (P = 0.004) BP compared with saline-challenged controls. Higher mean BP significantly correlated to increased total respiratory system resistance (R2 = 0.266, P = 0.002), driven by an association with parenchymal tissue dampening (R2 = 0.166, P = 0.016). HDM relative to saline-challenged controls increased the expression of serum IL-6 (P = 0.008), but no relationships of systemic BP with IL-6 or any other cytokines were found. CIH did not alter the allergen-induced responses on BP, although it tended to increase the expression of serum IL-6 (P = 0.06) and monocyte chemoattractant protein-1 (MCP-1, P = 0.09), regardless of HDM challenge. Chronic allergen-induced airway inflammation results in systemic hypertension that is correlated to the degree of distal airway obstruction induced by the allergen. These effects do not appear to be explained by the associated systemic inflammation.

Pulmonary delivery of ORMDL3 short hairpin RNA – a potential tool to regulate allergen-induced airway inflammation

Aim/Purpose: Exposure to various allergens has been shown to increase expression of ORMDL3 in the lung in models of allergic asthma. Studies using genetically modified (transgenic or knock out) mice have revealed some of the functions of ORMDL3 in asthma pathogenesis, although amid debate. The goal of this study was to use targeted post-transcriptional downregulation of ORMDL3 in allergen-challenged wild-type (WT) mice by RNA interference to further elucidate the functional role of ORMDL3 in asthma pathogenesis and evaluate a potential therapeutic option.Methods: Allergen (ovalbumin [OVA])-challenged WT mice were administered intranasally (i.n) with a single dose of five short hairpin RNA (shRNA) constructs with different target sequence for murine ORMDL3 cloned in a lentiviral vector or with the empty vector (control). Mice were evaluated for allergen-induced airway hyperresponsiveness (AHR) and various features of airway inflammation after 72 hours.Results: I.n administration of a single dose of ORMDL3 shRNAs to OVA-challenged mice resulted in reduction of ORMDL3 gene expression in the lungs associated with a significant reduction in AHR to inhaled methacholine and in the number of inflammatory cells recruited in the airways, specifically eosinophils, as well as in airway mucus secretion compared to OVA-challenged mice that received the empty vector. Administration of ORMDL3 shRNAs also significantly inhibited levels of IL-13, eotaxin-2 and sphingosine in the lungs. Additionally, ORMDL3 shRNAs significantly inhibited the allergen-mediated increase in monohexyl ceramides C22:0 and C24:0.Conclusions: Post-transcriptional down regulation of ORMDL3 in allergic lungs using i.n-delivered ORMDL3 shRNA (akin to inhaled therapy) attenuates development of key features of airway allergic disease, confirming the involvement of ORMDL3 in allergic asthma pathogenesis and serving as a model for a potential therapeutic strategy.

Interplay Between the IL-33/ST2 Axis and Bone Marrow ILC2s in Protease Allergen-Induced IL-5-Dependent Eosinophilia.

Background: Eosinophils develop from CD34+ progenitor cells in the bone marrow under the influence of interleukin (IL)-5. Several cell types produce IL-5, including type 2 innate lymphoid cells (ILC2s). The alarmin cytokine IL-33 is known to activate ILC2s in mucosal tissues, but little is known about IL-33-responsive ILC2s in the bone marrow in allergen-induced airway inflammation.Methods: Wild type (WT) and Rag1 deficient (Rag1−/−) mice, which lack mature T and B cells, received intranasal doses of papain to induce acute allergic inflammation. In some experiments, mice were pre-treated with anti-IL-5 prior to the papain challenge. Furthermore, recombinant IL-33 was administered to WT mice, Rag1−/− mice, lymphocyte deficient mice (Rag2−/−Il2rg−/−) and to ex vivo whole bone marrow cultures. Bone marrow eosinophils and ILC2s were analyzed by flow cytometry. Eosinophil count was assessed by differential cell count and secreted IL-5 from bone marrow cells by ELISA.Results: Intranasal administration of papain or IL-33 increased the number of mature eosinophils in the bone marrow despite the absence of adaptive immune cells in Rag1−/− mice. In parallel, an increased number of eosinophils was observed in the airways together with elevated levels of Eotaxin-2/CCL24. Bone marrow ILC2s were increased after papain or IL-33 administration, whereas ILC2s was found to be increased at baseline in Rag1−/− mice compared to WT mice. An upregulation of the IL-33 receptor (ST2) expression on bone marrow ILC2s was observed after papain challenge in both Rag1−/− and WT mice which correlated to increased number of bone marrow eosinophilia. Furthermore, an increased number of ST2+ mature eosinophils in the bone marrow was observed after papain challenge, which was further dependent on IL-5. In addition, bone marrow-derived ILC2s from both mouse strains produced large amounts of IL-5 ex vivo after IL-33 stimulation of whole bone marrow cultures. In contrast, IL-33-induced bone marrow and airway eosinophilia were abolished in the absence of ILC2s in Rag2−/−Il2rg−/− mice and no production of IL-5 was detected in IL-33-stimulated bone marrow cultures.Conclusion: These findings establish bone marrow ILC2s and the IL-33/ST2 axis as promising targets for modulation of uncontrolled IL-5-dependent eosinophilic diseases including asthma.

Innate IL-17A Enhances IL-33-Independent Skin Eosinophilia and IgE Response on Subcutaneous Papain Sensitization

IL-33-activated group 2 innate lymphoid cells critically contribute to protease allergen-induced airway inflammation models. However, IL-33 is dispensable for a subcutaneous (s.c.) papain-induced skin inflammation model, suggesting distinct mechanisms between intranasal and s.c. sensitization. Here, we examined the role of IL-17A in the s.c. model. Papain-exposed skin produced IL-17A and an excess amount of a soluble decoy receptor for IL-33, with the latter being a possible reason for the independence of the s.c. model from IL-33. An IL-17A deficiency attenuated papain-induced skin eosinophilia and serum papain-specific IgE and IgG1 levels, whereas the s.c. administration of IL-17A with enzymatically inactive papain enhanced serum papain-specific IgE and IgG1 levels and T helper 2 development in draining lymph nodes in an IL-33-independent manner, suggesting IL-33-independent enhancement of papain-specific type 2 responses by IL-17A. The s.c. papain increased IL-17A+ γδ T cells in draining lymph nodes, approximately half of which were Vγ4+, as the majority of IL-17A+ cells, and increased Vγ5+ and Vγ4+ γδ T cells in the skin. Depletion of γδ TCR+ cells reduced T helper cytokine production in antigen-restimulated draining lymph node cells. These results suggest a novel role for IL-17A as an enhancer of skin eosinophilia and serum antigen-specific IgE production and for γδ T cells as an enhancer of T helper cell activation in the s.c. papain model.

Paediatric Recurrent Ear, Nose and Throat Infections and Complications: Can We Do More?

Recurrent respiratory tract infections (rRTIs), of which there are three main groups—otitis media, tonsillitis and sinusopathies—are very common in paediatric populations and are associated with significant morbidity and mortality due to complications. These infections substantially reduce quality of life for paediatric patients and their families and are a significant personal, medical and economic burden on the patients, the patients’ families and the healthcare system. Most rRTIs are of viral origin; however, indiscriminate use of antibiotics in their treatment has led to development of bacterial resistance. Effective management of rRTIs to reduce the burden of disease and to avoid overuse of antibiotics has become a great therapeutic challenge. New strategies for the management of paediatric rRTIs include focus on prevention using non-specific immunomodulators to boost the body’s natural defences against infection and to downregulate infection- and allergen-induced airway inflammation. The oral immunomodulator, OM-85, a bacterial lysate, acts on the innate and adaptive branches of the immune system, conferring protection against viral and bacterial infections, and controls inflammation, thereby reducing tissue damage. OM-85 has demonstrated good tolerability and clinical efficacy in reducing the number and duration of RTIs in children with recurrent airway infections. It has also been reported to reduce the use of concomitant medications, including antibiotics, time to cure and school absenteeism. OM-85 is efficacious and well tolerated when administered concomitantly with inactivated influenza vaccine (IIV) and has been shown to reduce wheezing attacks induced by RTI in young children. Clinical results show that the greater the risk of rRTIs, the greater the benefit with OM-85. OM-85 may be considered a promising tool to add to the limited armamentarium of the ear, nose and throat (ENT) physician dealing with rRTIs and their complications, such as recurrent wheeze and asthma inception.

Goat Milk Consumption Enhances Innate and Adaptive Immunities and Alleviates Allergen-Induced Airway Inflammation in Offspring Mice.

Goat milk (GM), as compared to cow milk (CM), is easier for humans to digest. It also has antioxidant and anti-inflammatory effects and can improve minor digestive disorders and prevent allergic diseases in infants. It is unclear whether GM consumed in pregnant mothers has any protective effects on allergic diseases in infants. In this experimental study with mice, we found GM feeding enhanced immunoglobulin production, antigen-specific (ovalbumin, OVA) immune responses, and phagocytosis activity. The GM-fed mice had an increasing proportion of CD3+ T lymphocytes in the spleen. Splenocytes isolated from these animals also showed significantly increased production of cytokines IFN-γ and IL-10. More importantly, GM feeding during pregnancy and lactation periods can confer protective activity onto offspring by alleviating the airway inflammation of allergic asthma induced by mite allergens. There was a remarkably different composition of gut microbiota between offspring of pregnant mice fed with water or with milk (GM or CM). There was a greater proportion of beneficial bacterial species, such as Akkermansia muciniphila, Bacteroides eggerthii, and Parabacteroides goldsteinii in the gut microbiota of offspring from GM- or CM-fed pregnant mice compared to the offspring of water-fed pregnant mice. These results suggested that improving the nutrition of pregnant mice can promote immunological maturation and colonization of gut microbiota in offspring. This mother-to-child biological action may provide a protective effect on atopy development and alleviate allergen-induced airway inflammation in offspring.

Probiotics Attenuates Allergic Airway Inflammation via Downregulation of Hypoxia Signaling

A recent study showed probiotics had been advocated for the prevention and treatment of allergic disease. However, the immunomodulatory effects and mechanism of probiotics on allergic airway disease such as asthma are unknown. This study investigated whether oral administrations of probiotics inhibited allergen-induced airway inflammation in a mouse asthma model. BALB/c mice were randomly assigned to the six experimental groups: controls; OVA-induced asthmatic mice; and OVA-induced mice orally administered with one of the two probiotics (Lactobacillus paracasei or Bacillus clausii, dose of 1×106 or 5×106 CFU, respectively). Effects of treatment were analyzed based on serum antibody levels, bronchoalveolar lavage fluids (BALF) cell counts, lung histology, lung cytokine levels, and airway hyperreactivity (AHR). OVA-sensitized mice treated with probiotics had significantly reduced numbers of eosinophils and total cell in BALF compared to the OVA group (p<0.05). Probiotics also significantly reduced eosinophil infiltration, which decreased AHR and inflammation in the lung tissues of OVA-sensitized mice. Probiotics also decreased the levels of Th2 cytokines in BALF. A real-time PCR analysis of the expression of genes in lung tissues showed that probiotics could significantly decrease the levels of HO-1 and HIF-1α expression compared to the levels in asthmatic mice (p<0.05). These results indicate that probiotics attenuate airway inflammation and hyperresponsiveness by regulating HIF-1α signaling in allergic airway disease. This finding suggests that probiotics have a role in the progress of the allergic disease, and might be used as a therapeutic tool of allergic airway inflammation.

MiR-511-3p protects against cockroach allergen-induced airway inflammation

miR-511-3p protects against cockroach allergen-induced airway inflammation

Requirement for neuropeptide Y in the development of allergen-induced airway hyperresponsiveness and inflammation

Requirement for neuropeptide Y in the development of allergen-induced airway hyperresponsiveness and inflammation

Mucosal-associated invariant T cells restrict allergic airway inflammation

We report that MAIT cells repress group 2 innate lymphoid cell activation and restrict allergen-induced airway inflammation and airway hyperresponsiveness.

Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-\u03b1

Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/− mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.

IL-35 Inhibited Th17 Response in Children with Allergic Rhinitis

Objective: Previous studies have proved that Th17 (T helper 17) cell subsets, a unique proinflammatory CD4+ T cell lineage, are deeply involved in the pathophysiology of allergic rhinitis (AR). IL-35, secreted mainly by natural Treg (nTreg) and depending on the expression of Foxp3, can effectively alleviate allergen-induced specific airway inflammation. However, the regulation of IL-35 in AR is not clear. Methods: Twenty AR children and 20 healthy controls were enrolled. The expression of serum IL-35 protein was detected and the correlation with Th17 cytokines (IL-17, IL-23, IL-27) expression was analyzed by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cells were prepared and stimulated by IL-35 to explore its effect on Th17 inflammation. Results: Serum IL-35 levels in AR were negatively correlated with serum IL-17 and IL-23 levels in AR. Recombinant IL-35 inhibits the Th17 response of PBMCs, which were mediated by the mitogen-activated protein kinase (MEK) and c-Jun N-terminal kinase (JNK) pathways. Conclusions: Our data demonstrate that IL-35 can inhibit Th17 response in AR through MEK and JNK pathways.

Bitter Taste Receptors: an Answer to Comprehensive Asthma Control?

Asthma is marked by peculiar pathological features involving airway contraction, an impinging inflammation in the lungs, and an inexorably progressive remodeling of pulmonary architecture. Current medications for management of asthma exacerbations fail to optimally mitigate these pathologies, which is partly due to the intrinsic heterogeneity in the development and progression of asthma within different populations. In recent years, the discovery of the ectopic expression of TAS2Rs in extraoral tissues and different cell types, combined with significant strides in gaining mechanistic understanding into receptor signaling and function, has revealed the potential to target TAS2Rs for asthma relief. TAS2R activation leads to relaxation of airway smooth muscle cells and bronchodilation. In addition, findings from preclinical studies in murine model of asthma suggest that TAS2R agonists inhibit allergen-induced airway inflammation, remodeling, and hyperresponsiveness. In this review, we expand on the opportunity presented by TAS2Rs in the development of a comprehensive asthma treatment that overcomes the limitations set forth by current asthma therapeutics.

Huangqi–Fangfeng protects against allergic airway remodeling through inhibiting epithelial–mesenchymal transition process in mice via regulating epithelial derived TGF-β1

BackgroundLong-term exposure to aeroallergens such as house dust mite (HDM) could result in airway inflammation and airway remodeling, characteristic features of allergic asthma. Huangqi–Fangfeng (HF), an important “couplet medicines” of Yu–Ping–Feng–San (YPFS), mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. PurposeTo evaluate the effects of HF on airway remodeling of allergic asthma in a murine model and to investigate the underlying mechanisms in vivo and in vitro. MethodsThe main components of HF were analyzed by HPLC. The HDM-induced asthma mice model was established to study the effects of HF on airway inflammation and airway remodeling in vivo. Enhanced pause (Penh) index value was used as an indicator of airway hyper-reactivity. Bronchoalveolar lavage fluid (BALF) was processed for differential cell counting and determination of cytokines production. The lungs were fixed in 4% paraformaldehyde for histological examination after staining with H&E, trichrome and IHC. Production of interleukin (IL)-4, IL-5, IL-13, and transforming growth factor beta-1 (TGF-β1) in BALF and lung tissues, IgE in serum were measured by ELISAs. Expression of epithelial markers and mesenchymal markers were detected by immunohistochemistry and western blots. The effects of HF and its components on epithelial-mesenchymal transition (EMT) were detected in human bronchial epithelial cells (16HBE) treated with TGF-β1 and HDM. ResultsThe main components of Huangqi–Fangfeng detected by HPLC were Calycosin, Formononetin and Cimifugin. In HDM-induced allergic asthma mice model, respiratory exposure to HDM lead to airway hyperresponsiveness and thickening of the smooth muscle layer in the airway. TGF-β1 levels increased in mice airways while epithelial cells lost expression of E-cadherin and gained expression of the mesenchymal proteins N-cadherin, α-SMA and collagen І. These changes were relieved by treatment with HF. Furthermore, restored epithelial markers expression treated with individual components were also detectable in 16HBE cells. ConclusionThese results demonstrated that Huangqi–Fangfeng protected against allergic airway remodeling through inhibiting epithelial–mesenchymal transition process in mice via regulating epithelial derived TGF-β1.

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats.

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresponsiveness by inhibiting UPR transducers.

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

A proposed role for Interleukin-6 in the modulation of Th2 asthmatic responses

Abstract The incidence of allergic asthma in the United States and other industrialized countries has been increasing over the past few decades. One proposed explanation for this increase is the hygiene hypothesis, which states that a lack of early childhood exposure to high levels of environmental lipopolysaccharide (LPS) endotoxins from gram-negative bacteria increases the susceptibility to developing allergic diseases. Our lab has recently shown that LPS can indeed reduce Th2-driven, allergen-induced airway inflammation by inducing the up-regulation of the transcription factor T-bet in responding allergen-specific T cells, which we found was required to prevent the Th2 cell differentiation program. Studies have shown that like LPS, interleukin-6 (IL-6) reduces Th2 cell responses in asthma models. Due to these findings, our lab is now investigating the role of IL-6 in LPS-mediated Th2 cell suppression. In addition, some evidence suggests that IL-12 and IL-18 produced by dendritic cells are involved in the induction of T-bet by upregulating IFN-γ in T cells and other lymphoid cells. Here, we investigate the interplay of these cytokines in a house dust mite-induced asthma model in C57BL/6 (B6) mice. Through studies with IL-6 knock out and IL-6 receptor knock out B6 mice, we have shown that IL-6 modulates the expression of the IL-18 receptor on T cells, thus affecting the synergy of IL-18 and IL-12 to induce T-bet and prevent Th2 responses. We hypothesize that IL-6 affects T cell ability to respond to these cytokines by influencing the thresholds of IL-18 and IL-12 needed for T cell responses.

The transcriptional repressor Blimp-1 promotes Th2 development and lung inflammatory disease in a house dust mite induced model of allergic asthma

Abstract Asthma is a T cell-mediated chronic inflammatory lung disease that is thought of as a type 2/Th2 disease, yet precisely how Th2 cell development in the lung is initiated is unknown. Blimp-1 is a transcriptional repressor that regulates effector T cell responses to constrain T cell-mediated autoimmunity. We describe Blimp-1 as an unexpected regulator of allergen-induced airway inflammation that is critical to promote Th2 cell development in the lung and subsequent airway inflammation. Using a house dust mite (HDM) antigen model to drive allergic lung disease, we show that the T cell specific absence of Blimp-1 leads to reduced lung inflammation, a significant decrease in eosinophil recruitment to the lung tissue, and a near absence of Th2 cells in the lung. Intriguingly, Th1 and Th17 responses are intact, suggesting Blimp-1 is specifically required for Th2 differentiation in this model. Furthermore, despite a lack of Th2 cells in the lung, IgE responses are intact, dissociating IL-4-mediated antibody driven responses from Th2 cells in the lung. Bcl6 expression is increased in both the draining lymph node and lung and using T cell specific Bcl6 and Blimp-1 double deficient mice, we find that Th2 cells are restored when Bcl6 is deleted in addition to Blimp-1. Bcl6 is a potent repressor of GATA3, suggesting Blimp-1 acts to indirectly promote GATA3 expression by suppression of Bcl6. Furthermore, we show that STAT3 signaling in T cells is responsible to upregulate Blimp-1 and subsequent Th2 development, implicating this pathway as a possible therapeutic target. Taken together, our data suggests Blimp-1 plays an unexpected and context-dependent role in allergic lung inflammation to promote Th2 cell differentiation and subsequent lung disease.

Dimethyl fumarate attenuates T helper type 2 (Th2) -mediated allergic airway inflammation by modulating dendritic cell function

Abstract Dendritic cells (DCs) are primary antigen presenting cells in lungs that promote Th2 cell mediated immunity to house dust mite (HDM) allergen. DCs are attractive therapeutic targets to modulate allergen-induced airway inflammation and adaptive immune responses. Dimethyl fumarate (DMF) are methyl esters of fumaric acid and regulates immune cell differentiation and effector functions. However, the effect of DMF on lung DCs has not yet been addressed. Here, we investigated the effect of DMF treatment employing murine model of HDM-induced experimental allergic asthma and DC adoptive transfer experiment. We show that local DMF application attenuates airway inflammation, mucous cell hyperplasia, and airway resistance to increasing dosage of inhaled methacholine. Notably, DMF administration in the allergen challenge phase significantly inhibited the lung recruitment of CD11b+ conventional DCs (cDC2) and suppressed Th2 cytokine producing IL4, IL5, and IL13 CD4+ T cells. In lung draining mediastinal lymph node (mLNs), DMF treatment significantly induces CD4+T regulatory (Tregs) cells. Moreover, prior to administration of fluorescent-labeled HDM, single DMF application to naïve mice impeded the migration of CD11b+ cDC2 to the draining mLNs. Adoptive transfer of DMF treated CD11c+ HDM-pulsed DCs to naïve mice with subsequent intranasal HDM-challenge similarly attenuates the features of airway inflammation. Collectively, our findings suggest that local DMF application modulates lung DCs function, thereby attenuates airway inflammation and is a potent antiasthmatic therapeutic agent.