Tohoku J. Exp. Med., 2018 November, 246(3)

Maternal Separation as Early-Life Stress Causes Enhanced Allergic Airway Responses by Inhibiting Respiratory Tolerance in Mice

RYUSUKE OUCHI,1 TASUKU KAWANO,1 HITOMI YOSHIDA,1 MASATO ISHII,1 TOMOMITSU MIYASAKA,1 YUICHI OHKAWARA,2 MOTOAKI TAKAYANAGI,1 TOMOKO TAKAHASHI1 and ISAO OHNO3

1Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
2Division of Experimental Allergy and Immunology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
3Center for Medical Education, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan

Epidemiologic studies indicate that exposure to psychosocial stress in early childhood is a risk factor of adult-onset asthma, but the mechanisms of this relationship are poorly understood. Therefore, we examined whether early-life stress increases susceptibility to adult-onset asthma by inhibiting the development of respiratory tolerance. Neonatal BALB/c female mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA and the adjuvant aluminum hydroxide. Maternal separation (MS) was applied as an early-life stressor during the induction phase of immune tolerance. The mice were challenged with OVA aerosol in adulthood, and allergic airway responses were evaluated, including airway hyper-responsiveness to inhaled methacholine, inflammatory cell infiltration, bronchoalveolar lavage fluid levels of interleukin (IL)-4, IL-5, and IL-13, and serum OVA-specific IgE. We then evaluated the effects of MS on the development of regulatory T (Treg) cells in bronchial lymph nodes (BLN) and on splenocyte proliferation and cytokine expression. In mice that underwent MS and OVA tolerization, the allergic airway responses and OVA-induced proliferation and IL-4 expression of splenocytes were significantly enhanced. Furthermore, exposure to MS was associated with a lower number of Treg cells in the BLN. These findings suggest that exposure to early-life stress prevents the acquisition of respiratory tolerance to inhaled antigen due to insufficient Treg cell development, resulting in Th2-biased sensitization and asthma onset. We provide the evidence for inhibitory effects of early-life stress on immune tolerance. The present findings may help to clarify the pathogenesis of adult-onset asthma.

Key words —— allergic asthma; early life stress; immune tolerance; regulatory T cell; Th2 immune polarization

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Tohoku J. Exp. Med., 2018, 246, 155-165

Correspondence: Tasuku Kawano, Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.

e-mail: t-kawano@tohoku-mpu.ac.jp