Abstract
T-helper (Th)17 cell responses are important for the development of neutrophilic inflammatory disease. Recently, we found that acetyl salicylic acid (ASA) inhibited Th17 airway inflammation in an asthma mouse model induced by sensitization with lipopolysaccharide (LPS)-containing allergens. To investigate the mechanism(s) of the inhibitory effect of ASA on the development of Th17 airway inflammation, a neutrophilic asthma mouse model was generated by intranasal sensitization with LPS plus ovalbumin (OVA) and then challenged with OVA alone. Immunologic parameters and airway inflammation were evaluated 6 and 48 h after the last OVA challenge. ASA inhibited the production of interleukin (IL)-17 from lung T cells as well as in vitro Th17 polarization induced by IL-6. Additionally, ASA, but not salicylic acid, suppressed Th17 airway inflammation, which was associated with decreased expression of acetyl-STAT3 (downstream signaling of IL-6) in the lung. Moreover, the production of IL-6 from inflammatory cells, induced by IL-17, was abolished by treatment with ASA, whereas that induced by LPS was not. Altogether, ASA, likely via its acetyl moiety, inhibits Th17 airway inflammation by blockade of IL-6 and IL-17 positive feedback.
Highlights
Asthma is a complex syndrome with many clinical phenotypes; its major characteristics include a variable degree of airflow obstruction, airway hyperresponsiveness, and eosinophilic or non-eosinophilic inflammation.[1]
Effects of acetyl salicylic acid (ASA) on the development of Th17 airway inflammation in IFN-c-deficient mice Previous experimental evidence indicated that ASA treatment during allergen challenge inhibited Th17 airway inflammation, but not Th1 inflammation, in a neutrophilic asthma model induced by airway sensitization with LPS-containing allergens.[14]
Challenge showed that lung infiltration of inflammatory cells induced by sensitization with LPS-containing OVA was significantly lower in IFN-g À/ À mice treated with ASA than in IFN-g À/ À mice treated with a sham control, whereas this phenotype was similar in IL-17A À/ À and WT mice after ASA
Summary
Asthma is a complex syndrome with many clinical phenotypes; its major characteristics include a variable degree of airflow obstruction, airway hyperresponsiveness, and eosinophilic or non-eosinophilic inflammation.[1] Severe persistent and/or difficult-to-control asthma may be associated with neutrophilic airway inflammation, whereas mild and moderate asthma may be related to eosinophilic airway inflammation.[1,2] In terms of asthma immunopathogenesis, airway inflammation in asthma patients can be categorized according to the involvement of particular CD4 þ T cell subsets, including T-helper (Th)[1], Th2 and Th17.3. In terms of Th17 polarization, signal transducer and activator of T cells (STAT)[3] and retinoid-related orphan receptor (ROR)gt are important transcription factors.[6,7] Induction of RORgt is dependent on STAT3 signaling, which is preferentially activated by IL-6.8
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