Abstract
Abstract Early life adversity (ELA) is a risk factor in the onset and exacerbation of inflammatory disorders including allergy, asthma and chronic pain disorders such as irritable bowel syndrome (IBS). Our previous studies using murine and porcine models showed that mast cells (MCs), a key immune cell driving allergies and chronic pain disorders, display a hyperactive tissue phenotype in adult animals exposed to ELA. The mechanism by which ELA induces MC hyperactivity in adulthood remains unknown. The aim of this study was to determine if ELA programs bone marrow derived MC progenitors toward a hyperactive phenotype into adulthood by using an ELA model of neonatal maternal separation plus early weaning (NMSEW). Female pups (C57BL/6) were either raised normal handled (NH) or NMSEW. At 10 weeks, serum and mesenteric windows from jejunum were collected to evaluate histamine and tissue MC activation. Bone-marrow derived MCs (BMMCs) from mice were harvested and stimulated with IgE-DNP and IL33 to assess histamine and IL6 release, respectively. NMSEW mice exhibited increased serum histamine levels (~1.5 fold higher, P<0.05), mesenteric MC numbers (~1.5 fold higher, P=0.05) and MC activation (~2 fold higher, P<0.0001). BMMCs from NMSEW mice exhibited greater histamine content, IgE-mediated histamine release and IL33-stimulated IL6 release (P<0.001), compared with NH BMMCs. Our data demonstrates that ELA induces lasting changes in MC progenitors programming them toward a hyperactive phenotype and increased activation in tissue. Future studies will investigate the mechanisms by which ELA drives lasting hyperactivity of MC progenitors and tissue MC hyperactivity, and its role in MC-related disorders in adulthood.
Published Version
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