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- Enteric glial modulation of immune activation during inflammatory stress
- Chow, Aaron Kin Yeung
- Electronic Theses & Dissertations
Gastrointestinal (GI) disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome, and other functional GI disorders are major health concerns and account for about $26.4 billion in yearly costs in the United States alone. Many of these GI disorders manifest symptoms such as GI dysmotility, intestinal secretion and absorption dysfunction, and abdominal pain. Inflammation plays a major role in the pathogenesis of these diseases, and current therapies for many GI disorders aim...
Show moreGastrointestinal (GI) disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome, and other functional GI disorders are major health concerns and account for about $26.4 billion in yearly costs in the United States alone. Many of these GI disorders manifest symptoms such as GI dysmotility, intestinal secretion and absorption dysfunction, and abdominal pain. Inflammation plays a major role in the pathogenesis of these diseases, and current therapies for many GI disorders aim to regulate the activation and progression of the inflammatory cascade. However, due to a gap in knowledge in how the immune system is regulated within the GI tract, there remains a lack of effective treatments for these common GI disorders. Interactions between the nervous system and immune system point to neurons having important roles in immune modulation, but the mechanisms of neuro-immune regulation in the gut is not completely understood.The enteric nervous system (ENS) consists of enteric neurons and enteric glia arranged in plexuses embedded in the gut wall. This neural network is responsible for the normal secretomotor functioning of the GI tract, and the disruption of the ENS network alters GI functioning and underlies pathological GI symptoms. As part of the ENS, enteric glia work in tandem with enteric neurons to coordinate GI functions. In addition to their contributions to maintain normal secretomotor functioning of the GI tract, enteric glia are activated by immunomodulatory signals, they can secrete and respond to cytokines, can exert immunosuppressive effects, and share characteristics with antigen presenting cells. Therefore, we hypothesize that enteric glia play an active role in immune regulation in the ENS.In this dissertation, we specifically examine the role enteric glial cells play as an antigen presenting cell to regulate immune activation. Our results show that enteric glia have the machinery necessary to act as an antigen presenting cell and can express major histocompatibility complex (MHC) type II molecules during inflammatory stress to interact with T-lymphocytes. Enteric glial MHC II expression has functional relevance, as it modulates the activation in Th17 and Treg subtypes, but not Th1 or Th2 T-lymphocyte subtypes. Although MHC II molecules are typically associated with the expression of phagocytosed extracellular antigens, our results show that enteric glia do not readily phagocytose extracellular antigens. Instead, MHC II expression in enteric glia is mediated by autophagy. The activation of autophagic pathways is necessary, but not sufficient in eliciting enteric glial MHC II expression. Finally, although enteric glia regulate T-lymphocyte activation, cytokine levels at the whole organism or regional tissue levels remain unchanged, suggesting that enteric glial cytokine effects primarily operate at the local microenvironment level.Our findings provide support for enteric glial cells having an active role as an immunomodulator. Specifically, we show that enteric glia modulate T-lymphocyte activation via autophagy-mediated MHC II expression and propose a novel mechanism of neuro-immune modulation in the gut.