IL-1β Derived Th17 Immune Responses Are a Critical Factor for Neutrophilic-Eosinophilic Airway Inflammation on Psychological Stress-Induced Immune Tolerance Breakdown in Mice

INTRODUCTION: Asthma is an inflammatory reaction mediated by type 2 helper T (Th2) cells and is known to increase eosinophil levels. Our previous study showed that stress-related asthma can cause neutrophilic and eosinophilic airway inflammation by suppressing immune tolerance. However, the mechanism of stress-induced neutrophilic and eosinophilic airway inflammation remains unclear. Therefore, to elucidate the cause of neutrophilic and eosinophilic inflammation, we investigated the immune response during the induction of airway inflammation. In addition, we focused on the relationship between immune response modulation immediately after stress exposure and the development of airway inflammation. METHODS: Asthmatic mice were induced by three phases using female BALB/c mice. During the first phase, the mice were made to inhale ovalbumin (OVA) to induce immune tolerance before sensitization. Some mice were exposed to restraint stress during the induction of immune tolerance. In the second phase, the mice were sensitized with OVA/alum intraperitoneal injections. In the final phase, onset of asthma was induced through OVA exposure. Asthma development was evaluated based on airway inflammation and T-cell differentiation. Microarray and qPCR analyses were used to enumerate candidate factors to investigate the starting point of immunological modification immediately after stress exposure. Furthermore, we focused on interleukin-1β (IL-1β), which initiates these immune modifications, and performed experiments using its receptor blocker interleukin-1 receptor antagonist (IL-1RA). RESULTS: Stress exposure during immune tolerance induction increased eosinophil and neutrophil airway infiltration. This inflammation was associated with decreased T regulatory cell levels and increased Th2 and Th17 levels in bronchial lymph node cells. Microarray and qPCR analyses showed that the initiation of Th17 differentiation might be triggered by stress exposure during tolerance induction. IL-1RA administration during stress exposure suppressed neutrophilic and eosinophilic airway inflammation via Th17 reduction and Treg increase. CONCLUSIONS: Our results show that psychological stress causes both eosinophilic and neutrophilic inflammatory responses due to the breakdown of immune tolerance. Furthermore, stress-induced inflammation can be abolished using IL-1RA.