Sex-specific impact of early life stress on adult lung inflammatory response after LPS and Poly I:C exposures

Biological sex influences the development and function of the immune system, shaping responses to infection through both innate and adaptive mechanisms. Early life stress can disrupt immune development through long-term changes in the hypothalamic-pituitary-adrenal (HPA) axis. Neonatal maternal separation (NMS) is an established model of early life adversity that mimics theses effects with sex-specific effects on physiological outcomes. To study how NMS alters immune responses to infection, newborn rats were separated from their mother for 3 h per day from post-natal day 3 to 12, whereas controls were undisturbed. Lung immune response was evaluated at 8 weeks old using LPS, which models gram-negative bacteria infection, and Poly I: C mimicking viral infection; both inducing activation of innate immune cells that play a role in the activation of adaptive immune response. Immune cell populations of broncho-alveolar lavage, lungs and spleen were measured by flow cytometry. In addition to sex differences of inflammatory responses, NMS increased broncho-alveolar lavage neutrophilia after Poly I:C and LPS exposure in males. Furthermore, accumulation of macrophages, neutrophils and natural killer cells in the airways of NMS animals was modulated in a sex- and stimulus-specific fashion. In addition, NMS also induced systemic immune modulation, as observed by the increased proportion of spleen NK cells in NMS male. Thus, our data suggest that early life stress exerts sexually dimorphic effects on immune cells and increases the risk of respiratory tract infections later in life.