BackgroundAsthma is a major public healthcare burden, affecting over 300 million people worldwide. While there has been great progress in the treatment of asthma, subsets of patients who present with airway neutrophilia, often have more severe disease, and tend to be resistant to conventional corticosteroid treatments. The receptor for advanced glycation endproducts (RAGE) plays a central role in the pathogenesis of eosinophilic asthma, however, it’s role in neutrophilic asthma remains largely uninvestigated.MethodsA mouse model of severe steroid resistant neutrophilic airway disease (SSRNAD) using the common fungal allergen Alternaria alternata (AA) was employed to evaluate the effects of genetic ablation of RAGE and pharmacological inhibition of the NLRP3 inflammasome on neutrophilic airway inflammation.ResultsAA exposure induced robust neutrophil-dominant airway inflammation and increased BALF levels of Th1/Th17 cytokines in wild-type mice, which was significantly reduced in RAGE-/- mice. Serum levels of IgE and IgG1 were increased similarly in both wild-type and RAGE-/- mice. Pharmacological inhibition of NLRP3 blocked the effects of AA exposure and NLRP3 inflammasome activation was RAGE-dependent. Neutrophil extracellular traps were elevated in the BALF of wild-type but not RAGE-/- mice and an atypical population of SiglecF+ neutrophils were identified in the BALF. Lastly, time-course studies found that RAGE expression promoted sustained neutrophil accumulation in the BALF of mice in response to AA.
Asthma is a major public health burden, affecting nearly 400 million people worldwide, with its prevalence steadily increasing. A growing number of populations with more severe disease are resistant to conventional therapies and are in need of novel preventative and therapeutic intervention strategies. Asthmatics with increased neutrophilia, usually have worse symptoms, more frequent exacerbations, and are insensitive to corticosteroids. Recent studies have demonstrated a critical role for the NLRP3 inflammasome in driving severe steroid‐resistant neutrophilic airway disease (SSRNAD). We have previously demonstrated a critical role for the receptor for advanced glycation endproducts (RAGE) in eosinophilic asthma, however, clinical studies indicate a potential role for RAGE in neutrophilic asthma. Therefore, in this study we have examined the role of RAGE in promoting experimental allergen‐driven SSRNAD. Here, mice are subjected to an experimental model of SSRNAD using complete freund’s adjuvant with Alternaria alternata extract (AA) during sensitization, followed by intranasal challenge with saline or AA. Exposure to AA induced strong neutrophil‐dominant inflammation as well as elevated levels of Th1/Th17 cytokines in the bronchoalveolar lavage fluid (BALF) of wild‐type (WT) but not RAGE‐KO mice. In addition, administration of NLRP3 and Caspase‐1 inhibitors also significantly reduced these features in the lungs. AA exposure elevated levels of NLRP3 and cleaved caspase‐1 in whole lung and BALF cells and increased levels of IL‐1b and IL‐6 in the BALF of WT but not RAGE‐KO mice. Interestingly, we found that circulating levels of IgE and IgG1 were increased in both WT and RAGE‐KO mice and were not affected by treatment with NLRP3 or Caspase‐1 inhibitors, suggesting humoral responses are independent of both RAGE and NLRP3. Moreover, while AA exposure increased lung levels of IL‐17A‐producing CD4 and CD8 T cells, there was a ten‐fold higher increase in a population of IL‐17A‐producing non‐conventional T cell/non‐B cells, suggesting that innate immune responses may be the driving factor of this neutrophilic inflammation. We also found elevated levels of citrullinated histone H3, which is a marker of neutrophil extracellular traps (NETs), in the BALF of WT, but not RAGE‐KO mice and inhibition of NETs reduced airway neutrophilia. Overall, these studies demonstrate that RAGE is a critical mediator of the innate immune response to allergens, promoting NLRP3 inflammasome activation and Th1/Th17‐driven inflammation, making RAGE an intriguing therapeutic target to reduce aberrant neutrophilia in airway disease.
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