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The role of the ionotropic glutamate receptor NMDAR on α ß T cells of the intestinal mucosa in an experimental murine model

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Author(s):
Marília Garcia de Oliveira
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Jean Pierre Schatzmann Peron; Alessandro dos Santos Farias; Vinicius de Andrade Oliveira; Marco Aurelio Ramirez Vinolo
Advisor: Jean Pierre Schatzmann Peron
Abstract

Ganglionic plexuses formed by interconnecting networks between neurons of the enteric nervous system are present in the muscular and submucosal layers of the small and large intestines. These neurons secrete several inhibitory and excitatory neurotransmitters, including glutamate, and their innervations reach the lamina propria of intestinal mucosa. Such neurotransmitters play a key role in intestinal motility and homeostasis through their interactions with intestinal epithelial cells. Recently, it has been discovered that T cells express receptors for neurotransmitters, including the ionotropic glutamate receptor NMDAR. Most lymphocytes found in the body are located within the intestinal mucosa and these cells play important roles in local tolerance to microbiota and food antigens. However, little is known about the role of NMDAR on T cells, especially in the intestinal mucosa. Therefore, we decided to initially investigate the role of NMDAR in T lymphocytes, through its specific deletion, in intestinal homeostasis. Conceptually, we show in this work the efficiency of the specific deletion of NMDAR on CD4+ and CD8+ α ß T cells in lymphoid tissues such as the spleen, thymus, mesenteric and cecal lymph nodes, as well as in the lamina propria and intraepithelial compartment of both intestines of Cd4CrexGrin1f/f mice. Such deletion favors gene expression of other NMDAR subunits, such as NR2c and NR2d in the spleen and mesenteric lymph nodes, without interfering with intestinal permeability and transit. Furthermore, we demonstrate that naïve Cd4CrexGrin1f/f mice have altered distribution of CD4+ and CD8+ T cells, even γ δ T cells, in the thymus, spleen, and mesenteric and cecal lymph nodes. Although we did not observe differences in the lamina propria and intraepithelial compartment of the intestines in Cd4CrexGrin1f/f mice in the naïve condition, we decided to also investigate the role of NMDAR in α ß T cells upon inflammatory stimulus through experimental models of acute and chronic colitis. In acute DSS-induced colitis, an increase of CD4+ T cells and a decrease of CD8+ T cells frequencies in the lamina propria of the cecum and colonic intraepithelial compartment were observed in Cd4CrexGrin1f/f mice. In turn, CD4+ T cells from the lamina propria of the cecum of these mice produced more IL-17. In addition, we also showed changes in the frequency of γ δ T cells in cecum and colon lamina propria, dependent on this deletion. In chronic colitis model induced by multiple cycles of DSS, specific deletion of NMDAR in α ß T cells resulted in reduced frequency of CD4+ T cells and increased IFN-γ production by these cells in the colonic lamina propria. Finally, we also evaluated a chronic colitis model caused by adoptive transfer of naive CD4+ T cells to Rag1-/- mice. The transfer of NMDAR-depleted CD4+ T cells generated an increase in the frequency of CD4+ T cells, as well as a reduction in the expression of CD103 and in the consecutive production of IL-17 and IFN-γ by these cells in the mesenteric and cecal lymph nodes when compared to control group. Although these alterations are suggestive of loss of intestinal homeostasis, as well as in the model of acute and chronic colitis induced by DSS, we also did not observe differences in the macroscopic and microscopic parameters referring to chronic inflammation in Cd4CrexGrin1f/f mice. Taken together, our data suggest the involvement of NMDAR expressed by α ß T cells in controlling the intestinal homeostasis and during inflammatory bowel diseases, mainly acute colitis, without compromising the induction of oral tolerance to Ovalbumin. (AU)

FAPESP's process: 18/10242-5 - The role of ionotropic glutamate receptor NMDA in innate and adaptive immune cells from intestinal mucosa in murine experimental model
Grantee:Marília Garcia de Oliveira
Support Opportunities: Scholarships in Brazil - Doctorate