The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs

Abstract

Background: Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed ''type-2 high'' asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated. Objective: The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine-induced signal transduction, airway inflammation, and mucus metaplasia in the lungs. Methods: Wild-type (WT) and RAGE knockout (RAGE 2/2) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine-induced effects. Results: Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE 2/2 mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells. Conclusions: This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2-high asthma.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model

“…RAGE has been shown to play an important role in asthma in studies using several types of asthma models. Recently, Perkins TN et al reports that RAGE is a crtical component of type 2 cytokine signaling, which is a driving force behind type 2-high asthma (Perkins et al 2019). Consistent with a previous study, TDI-induced mice in this study exhibited typical features of asthma (AHR, a Th2 response, and airway inflammation), while treatment with FPS-ZM1 attenuated the response (Yao et al 2016;Zhao et al 2018).…”

RAGE-induced asthma: A role for the receptor for advanced glycation end-products in promoting allergic airway disease

“…This suggests that signaling through RAGE is required for sustained STAT6 activation after stimulation through the IL-4/IL-13 receptor complex but not for initial phosphorylation of STAT6 (Fig 1, B). 9 As described above, RAGE binds many ligands that have been associated with the pathogenesis of allergic asthma. Because antagonization of key intracellular signaling events associated with asthma pathogenesis would have important therapeutic implications, Perkins et al 9 also explored the potential ligands mediating the ability of RAGE signaling to facilitate sustained signaling after T H 2 cytokine exposure.…”

“…7 Blocking HMGB1 in turn resulted in a partial decrease in BALF IL-25 and IL-33 levels and subsequent T H 2 responses on HDM rechallenge. 7 In this issue of the Journal, Perkins et al 9 examine the ability of RAGE to influence signaling of cytokines typically produced during robust T H 2 inflammation. Building on their own work demonstrating that RAGE-deficient mice did not demonstrate pulmonary accumulation of group 2 innate lymphoid cells or subsequent T H 2 inflammation after exposure to either Alternaria species extract or recombinant IL-33, 8 Perkins et al 9 here examine the capacity of IL-4 or IL-5/IL-13 to induce asthma-like disease in RAGE-deficient mice.…”

“…7 In this issue of the Journal, Perkins et al 9 examine the ability of RAGE to influence signaling of cytokines typically produced during robust T H 2 inflammation. Building on their own work demonstrating that RAGE-deficient mice did not demonstrate pulmonary accumulation of group 2 innate lymphoid cells or subsequent T H 2 inflammation after exposure to either Alternaria species extract or recombinant IL-33, 8 Perkins et al 9 here examine the capacity of IL-4 or IL-5/IL-13 to induce asthma-like disease in RAGE-deficient mice. Although daily intranasal challenges with either rIL-4 or a combination of rIL-5 and rIL-13 over a 4day period resulted in BALF eosinophilia, mucus production, and robust inflammatory gene expression in WT mice, this was nearly completely abrogated in RAGE-deficient mice and mice treated with a RAGE antagonist (FPS-ZM1).…”

“…Mechanistically, Perkins et al 9 demonstrate that reduced responsiveness to effector T H 2 cytokines observed in RAGEdeficient mice or after pharmacologic inhibition of RAGE was not due to altered levels of expression of the IL-4/IL-13 receptor components or protein levels of the downstream signaling mediator signal transducer and activator of transcription 6 (STAT6). Moreover, after a single in vivo pulmonary challenge with rIL-13, comparable levels of activated phosphorylated signal transducer and activator of transcription 6 (pSTAT6) were observed in the lung just after exposure (10 minutes to 1 hour).…”