Numerous observations have suggested that inflammatory bowel disease is a multifactorial process encompassing at least three major interacting elements: environmental conditions, altered mucosal immune function, and genetic susceptibility factors. While genetic factors and the environment are incredibly difficult to investigate in a controlled manner, attention and research investigation has focused on understanding mucosal immune responses with the working hypothesis being that intestinal inflammation results from a breakdown in immune tolerance to normal intestinal microbiota. While there is increasing understanding of the factors that contribute to the pathogenesis of intestinal inflammation, there is an urgent need for more thoroughly understanding protective factors that control inflammation in order to design more efficacious treatments. An important challenge remains the ability to maintain the critical balance between enforcing tolerance to normal commensal bacteria, while allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosal resident antigen presenting cells (APCs), particularly dendritic cells (DCs) and macrophages, hold great promise in this regard because they can uptake enteric bacteria, viruses, and protozoa and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. In essence, mucosal APCs are sentinels situated just beneath the epithelial barrier and are capable of initiating and orchestrating intestinal immune responses. Importantly, mucosal DC and macrophage function is closely integrated with overlying intestinal epithelial cells. This intact intestinal layer creates a critical, semi-permeable barrier that allows passage of luminal fluid and molecules between epithelial cells while tightly regulating the flux of the enteric microbiota. Alterations in the integrity of the intestinal epithelial barrier can have a profound impact on intestinal disease susceptibility. While there are associations between increased intestinal epithelial permeability predating the onset of intestinal inflammation, little is understood about how the epithelial barrier regulates innate and adaptive immune cells in the underlying lamina propria. Thus, a clear understanding of the consequences of increased intestinal epithelial permeability created by JAM-A deficiency on the function of lamina propria DCs and macrophages (Specific Aim 1) and detailed analysis of the outcome of JAM-A deficiency in regulation of immune responses during intestinal inflammation (Specific Aim 2) would represent major advancements toward the understanding and treatment of intestinal inflammation, as well as mucosal tolerance and immunity. The overall goal of this proposal is to gain a stronger fundamental understanding of how increased intestinal epithelial barrier permeability regulates the function of lamina propria antigen presenting cells in homeostasis and inflammation. The central hypothesis driving this research is that a """"""""leaky"""""""" intestinal epithelial barrier leads to dysfunction of intestinal lamina propria macrophages and dendritic cells and the development of intestinal inflammation.
The overall goal of this proposal is to gain a stronger fundamental understanding of how increased intestinal epithelial barrier permeability regulates the function of lamina propria antigen presenting cells in homeostasis and inflammation. The central hypothesis driving this research is that a leaky intestinal epithelial barrier leads to dysfunction of intestinal lamina propria macrophages and dendritic cells and the development of intestinal inflammation.
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| Khounlotham, Manirath; Kim, Wooki; Peatman, Eric et al. (2012) Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. Immunity 37:563-73 |
| Medina-Contreras, Oscar; Geem, Duke; Laur, Oskar et al. (2011) CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest 121:4787-95 |
| Denning, Timothy L; Norris, Brian A; Medina-Contreras, Oscar et al. (2011) Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J Immunol 187:733-47 |
