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

Abstract

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.

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

“…TNF- α migrating upregulate T-bet transcription factor in CD11b + DCs inducing IL-12 secretion which in turn prevents the Th2 cells differentiation [ 65 ]. It has also been found to be caused by underdeveloped Treg cells [ 66 ]. Additionally, neonatal BCG vaccination can inhibit allergic airway inflammation, by promoting T-regulatory immune response through enhanced expression of toll-like receptor 2 and 4 and PD-L1 on DC [ 67 ].…”

Moderate early life stress improves adult zebrafish (Danio rerio) working memory but does not affect social and anxiety‐like responses

“…ELS can be assessed behaviorally and biologically in rodents by using protocols such as maternal separation, postweaning social isolation, and peripubertal stress (Dunphy‐Doherty et al., 2018; Lyons, Parker, & Schatzberg, 2010; Ouchi et al., 2018; Tsuda, Yamaguchi, & Ogawa, 2011). Although high or chronic levels of stress may disturb brain development and affect behavior, acute activation of the body's stress response systems can adapt and increase chances of survival (Anda et al., 2006; De Bellis et al., 1999; Lupien, McEwen, Gunnar, & Heim, 2009; Maniglio, 2009; Pechtel & Pizzagalli, 2011; Spataro, Mullen, Burgess, Wells, & Moss, 2004).…”

Moderate early-life stress improves adult zebrafish (Danio rerio) spatial short-term memory but does not affect social and anxiety-like responses

“…ELS can be assessed behaviorally and biologically in rodents by using protocols such as maternal separation, post-weaning social isolation and peripubertal stress (Dunphy-Doherty et al, 2018; Lyons, Parker, & Schatzberg, 2010; Ouchi et al, 2018; Tsuda, Yamaguchi, & Ogawa, 2011). Although high or chronic levels of stress may disturb brain development and affect behavior, acute activation of the body’s stress response systems can adapt and increase chances of survival (Anda et al, 2006; De Bellis et al, 1999; Lupien, McEwen, Gunnar, & Heim, 2009; Maniglio, 2009; Pechtel & Pizzagalli, 2011; Spataro, Mullen, Burgess, Wells, & Moss, 2004).…”