Short‐term high‐fat diet feeding protects from the development of experimental allergic asthma in mice
Torsten SchröderAnna V. WieseFanny EnderKatharina M. QuellTillman VollbrandtJannis DuhnAnnika SünderhaufAxel KünstnerMaria E. Moreno‐FernandezStefanie DererZouhair AherrahrouIan LewkowichSenad DivanovicChristian SinaJörg KöhlYves Laumonnier
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Abstract Background A close association between obesity and asthma has been described. The nature of this association remains elusive, especially with respect to allergic asthma. Controversial findings exist regarding the impact of short‐term high‐fat diet (HFD) feeding on the development of allergic asthma. Objective To delineate the impact of short‐term HFD feeding on the development of experimental allergic asthma. Methods Female C57BL/6JRJ mice were fed with a short‐term HFD or chow diet (CD) for 12 weeks. Allergic asthma was induced by intraperitoneal OVA/alum sensitization followed by repeated OVA airway challenges. We determined airway hyperresponsiveness (AHR) and pulmonary inflammation by histologic and flow cytometric analysis of immune cells. Furthermore, we assessed the impact of HFD on dendritic cell (DC)‐mediated activation of T cells. Results Female mice showed a mild increase in body weight accompanied by mild metabolic alterations. Upon OVA challenge, CD‐fed mice developed strong AHR and airway inflammation, which were markedly reduced in HFD‐fed mice. Mucus production was similar in both treatment groups. OVA‐induced increases in DC and CD4 + T‐cell recruitment to the lungs were significantly attenuated in HFD‐fed mice. MHC‐II expression and CD40 expression in pulmonary CD11b + DCs were markedly lower in HFD‐fed compared to CD‐fed mice, which was associated in vivo with a decreased T helper (Th) 1/17 differentiation and Treg formation without impacting Th2 differentiation. Conclusions/clinical relevance These findings suggest that short‐term HFD feeding attenuates the development of AHR, airway inflammation, pulmonary DC recruitment and MHC‐II/CD40 expression leading to diminished Th1/17 but unchanged Th2 differentiation. Thus, short‐term HFD feeding and associated metabolic alterations may have protective effects in allergic asthma development.Keywords:
Allergic Inflammation
Abstract The prevalence of food allergies worldwide has increased recently. Epicutaneous sensitization to antigen could be a method to study food allergy. To clarify the mechanisms of food allergy, we established a mouse model of epicutaneous sensitization using ovalbumin ( OVA ). BALB /c mice were sensitized by three‐time application of OVA to tape‐stripped skin (1‐week sensitization at 2‐week intervals) and oral challenge of OVA undertaken. Rectal temperature was monitored. Blood and tissue (skin and jejunum) of challenged mice were taken. Numbers of mast cells ( MC s) and basophils were counted. Serum and/or tissue levels of OVA ‐specific IgE and IgG antibodies and several cytokines were measured using enzyme‐linked immunoassay kits. MC and basophil depletion experiments were undertaken. In OVA /epicutaneous‐sensitized and orally challenged mice, systemic anaphylaxis (as evidenced by reduced rectal temperature) was observed. Levels of OVA ‐specific IgE and IgG antibodies were increased in these mice, as were increased number of MC s and basophils. Serum levels of MC protease 1 were increased significantly. Basophil and MC depletion experiments revealed that they both participate in reactions. Increased production of thymic stromal lymphopoietin ( TSLP ) at skin sites of OVA sensitization was noted. We speculate that TSLP produced from epidermal cells during antigen sensitization can enable basophils to promote a T helper (Th)2 immune reaction, leading to and systemic anaphylaxis by antigen‐specific IgE‐bearing MC s. This TSLP ‐basophils‐ MC axis could be a novel therapeutic target against food allergy.
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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 antigen1,2. 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 asthma6,7. 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.
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Mouse models of allergic airway disease have greatly contributed to our understanding of disease induction and pathogenesis. Although these models typically investigate responses to a single antigen or allergen, humans are frequently exposed to a myriad of allergens, each with distinct antigenic potential.Given that airway exposure to ovalbumin (OVA), a prototypic innocuous antigen, induces inhalation tolerance, we wished to investigate how this response would be altered if OVA were encountered concurrently with a house dust mite extract (HDM), which we have recently shown is capable of eliciting a robust allergic airway inflammatory response that is mediated, at least in part, by granulocyte-macrophage colony-stimulating factor.Balb/c mice were exposed daily to HDM (intranasally) followed immediately by exposure to aerosolized OVA for 5 weeks. To allow the inflammatory response elicited by HDM to subside fully, mice were then allowed to rest, unexposed, for 8 weeks, at which time they were rechallenged with aerosolized OVA for 3 consecutive days.At this time, we observed a robust eosinophilic inflammatory response in the lung that was associated with an increase in bronchial hyperreactivity. Moreover, we documented significantly elevated serum levels of OVA-specific IgE and IgG(1) and increased production of the Th2 cytokines interleukin 4 (IL-4), IL-5, and IL-13 by splenocytes stimulated in vitro with OVA.Our data demonstrate the potential of a potent allergen such as HDM to establish a lung microenvironment that fosters the development of allergic sensitization to otherwise weak or innocuous antigens, such as OVA.
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Gender influences the incidence and/or the severity of several diseases and evidence suggests a higher rate of allergy and asthma among women. Most experimental models of allergy use mice sensitized via the parenteral route despite the fact that the mucosal tissues of the gastrointestinal and respiratory tracts are major sites of allergic sensitization and/or allergic responses. We analyzed allergen-specific Ab responses in mice sensitized either by gavage or intraperitoneal injection of ovalbumin together with cholera toxin as adjuvant, as well as allergic inflammation and lung functions following subsequent nasal challenge with the allergen. Female mice sensitized intraperitoneally exhibited higher levels of serum IgE than their male counterparts. After nasal allergen challenge, these female mice expressed higher Th2 responses and associated inflammation in the lung than males. On the other hand, male and female mice sensitized orally developed the same levels of allergen-specific Ab responses and similar levels of lung inflammation after allergen challenge. Interestingly, the difference in allergen-specific Ab responses between male and female mice sensitized by the intraperitoneal route was abolished in IKKβΔMye mice, which lack IKKβ in myeloid cells. In summary, the oral or systemic route of allergic sensitization and IKKβ signaling in myeloid cells regulate how the gender influences allergen-specific responses and lung allergic inflammation.
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The low affinity receptor for IgE (CD23) is reported to regulate immune and inflammatory events and as a result, it may have a role in the development of allergic airway inflammation and hyperresponsiveness (AHR). To test this hypothesis CD23-deficient mice were studied following different modes of allergic sensitization. Mice were actively sensitized either intraperitoneally with ovalbumin (OA)/alum or via the airways (10 days exposure to OA aerosol with no adjuvant). Passive sensitization was performed by intravenous injections of OA-specific IgE. Airway responsiveness, serum IgE and IgG levels were assessed together with airway inflammation. Passive sensitization followed by airway challenges resulted in increased OA-specific IgG and IgE in the serum of wild-type mice only, while both the CD23+ / + and CD23− / − groups developed tracheal smooth muscle hyperresponsiveness to electrical field stimulation, indicating that IgE/CD23-mediated immune functions may not be necessary for the development of allergic changes. Active sensitization of both CD23− / − and CD23+ / + mice resulted in increased serum levels of OA-specific IgE and IgG, airway eosinophilia and significant AHR when compared with nonsensitized mice. The genetic deficiency of CD23− / − mice not only failed to prevent but was associated with a significant increase of these responses. These results indicate that CD23 may not be essential for the development of allergen-induced AHR and further, that its presence may have some inhibitory effects on the allergic response.
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Platelet activation occurs in patients with allergic inflammation, and platelets can be activated directly by allergen via an IgE-dependent process. Platelets have been shown to activate APCs such as CD11c+ dendritic cells in vitro. Although CD11c+ dendritic cells are a requisite for allergen sensitization, the role of platelets in this process is unknown. In this study, we investigated whether platelets were necessary for allergen sensitization. Balb/c mice sensitized to ovalbumin were exposed to subsequent aerosolized allergen (ovalbumin challenge). We analyzed lung CD11c+ cell activation, colocalization with platelets, and some other indices of inflammation. The role of platelets at the time of allergen sensitization was assessed through platelet depletion experiments restricted to the period of sensitization. Platelets colocalized with airway CD11c+ cells, and this association increased after allergen sensitization as well as after subsequent allergen exposure. Temporary platelet depletion (>95%) at the time of allergen sensitization led to a suppression of IgE and IL-4 synthesis and to a decrease in the pulmonary recruitment of eosinophils, macrophages, and lymphocytes after subsequent allergen exposure. Furthermore, in mice previously depleted of platelets at the time of sensitization, the recovered platelet population was shown to have reduced expression of FcεRI. Pulmonary CD11c+ cell recruitment was suppressed in these mice after allergen challenge, suggesting that the migration of CD11c+ cells in vivo may be dependent on direct platelet recognition of allergen. We conclude that platelets are necessary for efficient host sensitization to allergen. This propagates the subsequent inflammatory response during secondary allergen exposure and increases platelet association with airway CD11c+ cells.
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Abstract Background The mechanism by which many monosensitized allergic individuals progress to polysensitization over time remains to be elucidated. Mouse models have contributed greatly to the understanding of sensitization to inhaled allergens in healthy airways but hardly any studies have addressed sensitization during established allergy. We hypothesized that an allergic inflammatory milieu might facilitate sensitization to inhaled allergens by the presence of mature dendritic cells ( DC s) and IL ‐4. Methods Mice with house dust mite ( HDM )‐induced allergic airway inflammation received a single intratracheal dose of ovalbumin ( OVA ), 2 days after the last HDM exposure. Ten days later, sensitization was assessed by rechallenge with OVA . We evaluated the following factors for their importance in neosensitization: (1) maturation and recruitment of DC s to the airways, (2) dependency on DC s using CD 11c DTR conditional knockout mice, (3) presence of ongoing airway inflammation by comparing sensitization at day 2 and day 14 after the last HDM exposure and (4) dependency on IL ‐4 by treatment with blocking antibodies. Results House dust mite ‐induced inflammation facilitated neosensitization to OVA . HDM ‐induced inflammation increased the number of airway DC s with a mature phenotype but a DC reduction of 93% did not inhibit sensitization. Neosensitization to OVA was dependent on ongoing inflammation and in particular on IL ‐4. Conclusions These findings show that HDM ‐induced allergic airway inflammation facilitates neosensitization to a second inhaled allergen in an IL ‐4‐dependent manner and provide insight into the underlying mechanism of the frequently observed progression to polysensitization in HDM ‐monosensitized individuals.
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Summary Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)‐mediated sensitization to environmental allergens. Yet, allergen‐specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6‐week‐, 6‐month‐, and 18‐month‐old female BALB /c mice, underwent epicutaneous sensitization with ovalbumin ( OVA ) or phosphate buffered saline ( PBS ), followed by an inhaled OVA challenge. Blood OVA ‐specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids ( BALF ) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6‐week‐old (young) and 6‐month‐old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18‐month‐old) mice compared to the other groups of mice. In addition, interleukin‐10 ( IL ‐10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA , possibly regulated by increased IL ‐10 levels.
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