Toll-like Receptor 7–triggered Immune Response in the Lung Mediates Acute and Long-Lasting Suppression of Experimental Asthma

Xirakia, Charoula; Koltsida, Ourania; Stavropoulos, Athanasios; Thanassopoulou, Artemis; Aidinis, Vassilis; Sideras, Paschalis; Andreakos, Evangelos

doi:10.1164/rccm.200908-1255oc

Cited by 99 publications

(114 citation statements)

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“…It activates APCs via the MyD88 pathway, leading to induction of proinflammatory cytokines and chemokines, especially large amounts of type 1 IFNs (22). In different rodent models of experimental asthma, R848 effectively inhibited the development of asthma and even reversed already established asthma symptoms after systemic and intranasal application (18,(23)(24)(25).…”

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confidence: 99%

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Jirmo

Daluege

Happle

et al. 2016

The Journal of Immunology

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Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell–driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN-γ and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death–ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN-γ whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.

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IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Jirmo

Daluege

Happle

et al. 2016

The Journal of Immunology

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“…R848 has been previously reported to be able to prevent disease onset when given before allergen challenge [8,13]. However, taking into account that original exposure to the sensitizing allergen remains Figure 1.…”

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confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Other investigators have reported the suppression of established asthma after in vivo treatment with the TLR7 agonist between a first and a second series of allergen challenges at an interval of 3-4 wk [8]. In a recent study, the protective treatment was given 1 day before a series of three challenges [13]. In this setting, the authors observed asthma suppression when mice received a repeated treatment with antigen 1 wk before the second series of challenges.…”

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confidence: 98%

“…These protective effects were observed after administration of R848 during the sensitization phase, whereas in mice having already mounted a primary allergic response, the treatment resulted in a marked reduction of secondary reactions following repeated allergen aerosol challenges mediated through 12]. Although IFN-g-producing NK cells have been held responsible for R848-induced asthma protection, it is now clear that they cannot solely account for the protection that is abolished neither by their depletion nor in IFN-g-deficient mice [13,14].Major cellular components driving asthmatic reactions include eosinophils and CD4 In the present study, we investigated the effect of the TLR7 agonist R848 in a murine experimental model of established allergic asthma. We provide evidence that this compound targets pulmonary Tregs, enabling them to exert a protective effect mediated mainly through TGF-b production.…”

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Treatment with the TLR7 agonist R848 induces regulatory T‐cell‐mediated suppression of established asthma symptoms

et al. 2011

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BelgiumThe evolution of allergic asthma is tightly controlled by effector and regulatory cells, as well as cytokines such as IL-10 and/or TGF-b, and it is widely acknowledged that environmental exposure to allergens and infectious agents can influence these processes. In this context, the recognition of pathogen-associated motifs, which trigger TLR activation pathways, plays a critical role with important consequences for disease progression and outcome. We addressed the question whether the TLR7 ligand resiquimod (R848), which has been shown to be protective in several experimental allergic asthma protocols, can also suppress typical asthma symptoms once the disease is established. To this end, we used an OVA-induced experimental model of murine allergic asthma in which R848 was injected after a series of challenges with aerosolized OVA. We found that the treatment attenuated allergic symptoms through a mechanism that required Tregs, as assessed by the expansion of this population in the lungs of mice having received R848, and the loss of R848-mediated suppression of allergic responses after in vivo Treg depletion. IL-10 provided only a minor contribution to this suppressive effect that was largely mediated through a TGF-b-dependent pathway, a finding that opens new therapeutic opportunities for the pharmacological targeting of Tregs.Key words: Asthma . TLR7 agonist . Tregs IntroductionEpidemiological studies have established that in recent decades the prevalence of allergic asthma has significantly increased in developed countries. Emerging evidence attests that early life events, including exposure to allergens and infections, are critical in programming effective regulatory pathways to maintain pulmonary homeostasis. Toll-like receptor (TLR) signaling contributes prominently to CD41 T-cell activation by connecting innate and acquired immunity. Mouse models of allergic asthma have long been used to dissect the immunological mechanisms leading to asthma, and despite the heterogeneity of experimental protocols in terms of strain differences, type and dose of antigen, time and route of administration, most 1992studies have provided evidence for protective effects of natural or synthetic TLR2, TLR4, or TLR9 ligands in allergen-induced lung inflammation [1][2][3][4][5]. Similarly, the synthetic ligand of TLR7, R848 (or resiquimod), has been reported to prevent typical respiratory syndromes (airway hyperresponsiveness) and allergic inflammation (recruitment of eosinophils to the lung, production of IgE Abs, and Th2-driven cytokine production) [5][6][7][8] in treated mice.R848 was initially developed as a potential antiviral agent and exerts its immunostimulatory function via mouse TLR7 as well as human TLR7 and TLR8 [9,10]. TLR7 stimulation activates APCs through the MyD88 pathway leading to the induction of proinflammatory cytokines, chemokines, and the release of large amounts of type I IFNs together with upregulation of costimulatory molecules [11]. In the rat, R848 has been shown to inhibit the inflammatory re...

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Toll‐Like Receptors

Allen

Trompette

Karp

2011

Inflammation and Allergy Drug Design

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Toll-like Receptor 7–triggered Immune Response in the Lung Mediates Acute and Long-Lasting Suppression of Experimental Asthma

Cited by 99 publications

References 42 publications

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Treatment with the TLR7 agonist R848 induces regulatory T‐cell‐mediated suppression of established asthma symptoms

Toll‐Like Receptors

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