 | Author: Vidhula Srinivasan, 2nd year undergraduate |
| Author: Stina Hench, 4th year graduate student Author: Natalia Duque-Wilckens postdoctoral researcher, | |
| Faculty mentor: Adam Moeser, Department of Physiology faculty member Faculty mentor: A.J. Robison – Department of Physiology faculty member |
Abstract:
Sepsis-associated encephalopathy (SAE), the most frequent type of encephalopathy in the ICU, is associated with long-term psychiatric disturbances and higher sepsis-induced mortality. The pathophysiology of SAE involves changes in neurotransmitter levels as well as increased neuroinflammation, but how peripheral inflammation triggers these responses in the central nervous system remains unknown. Mast cells, the effector cells of the innate immune system, are uniquely positioned to play a key role in linking peripheral to central inflammatory responses: they are distributed throughout the body, including the brain; they can rapidly respond to bacterial endotoxins; and they can release a plethora of mediators that can initiate and amplify inflammation as well as alter neuronal and glial function. Here we crossed the Mcpt5-Cre mouse line with the Cre-dependent B6-iDTR (Jax®) mice to render mast cells susceptible to diphtheria toxin (DTX) ablation to determine both the acute and developmental roles of mast cells in hypothermia and neuroinflammation induced by peripheral administration of Escherichia coli lipopolysaccharide (LPS). We injected the F1 litters with 30 ng/g DTX every 7 days starting at different developmental stages until adulthood, when animals were challenged with an intraperitoneal injection of 1 mg/kg of LPS. We found that animals in which mast cells were ablated starting before postnatal day 14, but not later, showed a more severe hypothermic response as well as increased levels of the inflammatory cytokine TNFα in the periaqueductal gray, suggesting an early developmental role for mast cells in neuroimmune networks underlying sepsis-induced hypothermia and neuroinflammation.