Sex Differences in Anatomic Plasticity of Gut Neuronal – Mast Cell Interactions
Luke A. Schwerdtfeger1 and Stuart A. Tobet1,2
1Department of Biomedical Sciences, 2School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado
Background: Neural regulation of immune components throughout the gut wall has gained increased attention. Mucosal immune cells, like mast cells among others, express neuropeptide receptors to vasoactive intestinal peptide (VIP), substance P, and many others. Mast cells are anatomically situated in close proximity to myriad enteric neuronal fibers in the gut mucosa, however, roles of specific neuropeptides in modulating function of immune components like mast cells in response to challenge with pathogens are relatively unknown. The present study tests the hypothesis that sex is a key variable in neural – immune signaling in the gut wall in healthy and perturbed tissue. Methods: We used an organotypic gut slice model that maintains the cellular diversity of the gut wall ex vivo. Slices were treated with selected pharmacological reagents that block neuronal function (e.g., tetrodotoxin) or VIP receptors prior to challenge with lipopolysaccharide (LPS) to assess their influence on anatomic plasticity of VIP-immunoreactive (IR) fibers and activation of mast cells as indicated by increases in size. Results: Sex differences were observed in the number of mucosal mast cells (c-kit/ACK2-IR) at baseline, regardless of treatment, with female ileum tissue having 46% more mast cells than males. After challenge with LPS, male mast cell counts rose to female levels (Figure 1E). There were no detectable sex differences in the baseline percent of mast cells within 1 µm of a VIP fiber. However, when challenged with LPS, tissue from males had an increased percentage of mast cells near a VIP fiber, while females did not change (Figure 1F). Further sex differences were observed in the size of mast cells with females having larger basal mast cell sizes (Figure 2A-D). Male mast cell sizes reached female levels after LPS treatment (Figure 2E-F). Conclusions: The present study demonstrates a close anatomical relationship of mast cells with VIP-IR neuronal fibers and suggests sex differences in neural-immune plasticity and in mast cell activation both basally and in response to challenge with LPS. These sex differences could potentially impact functional neuro-immune responses to pathogen, principally due to male cellular elements responding to LPS dosing with higher magnitude than female tissue. Additional data is needed to test the hypothesis that VIP has a functional role in regulating mast cell secretion of histamine in healthy and pathogen challenged states.
Breakout Room: Schwerdtfeger, Luke
View Poster: https://uclacns.org/symposium2021/7-Schwerdtfeger-Luke.pdf