Mucosal Healing of the Intestinal Epithelial Barrier

Agenda

* Presentation times are subject to change.

Abstracts

Tight Junction Barrier Loss: Friend or Foe?
Jerrold R. Turner, MD, PhD, Brigham and Women's Hospital, Departments of Pathology and Medicine (GI), and Harvard Medical School

The intestinal epithelial tight junction defines the paracellular permeability of non-ulcerated mucosae. Rather than an absolute barrier, the tight junction is a selectively permeable filter that can be modulated by both physiological and pathophysiological stimuli. Recent molecular and biophysical advances have defined two distinct trans-tight junction flux pathways, termed pore and leak, with different selectivities and capacities, as well as the non-selective unrestricted pathway that reflects epithelial damage. In vitro analyses have shown that the representative cytokines interleukin-13 (IL-13) and tumor necrosis factor (TNF) specifically enhance flux across pore and leak pathways by increasing expression of the tight junction protein claudin-2 or activating myosin light chain kinase, respectively. While distinguishable in vitro, tools to specifically assess flux across pore, leak, or unrestricted pathways are poorly developed and seldom used. This has led to confusion and errant interpretations of barrier loss in human disease and in vivo models. Work assessing these pathways, means to selectively measure and target them, and impact on intestinal infectious, immune-mediated, and toxic injury-related disease models will be discussed.

Epithelial Barrier Regulation by Inflammatory Bowel Disease Candidate Genes
Declan F. McCole, PhD, Division of Biomedical Sciences, University of California Riverside

Inflammatory bowel disease (IBD) is a multi-factorial condition characterized by elevated levels of pro-inflammatory cytokines such as TNF-α and IFN-γ. Genome-wide-association-studies (GWAS) have greatly expanded our understanding of the genetic contributions to IBD. Moreover, many of the identified genes have been shown to modulate various aspects of the intestinal barrier. Multiple GWAS have revealed that individuals with single nucleotide polymorphic mutations in the locus of the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene have an increased susceptibility to IBD. Loss-of-function mutations in PTPN2 are also associated with two other inflammatory diseases, Celiac disease and Type I diabetes. Interestingly, all of these conditions are associated with an increase in intestinal permeability prior to evidence of inflammation. We identified that the PTPN2 gene and its protein product, T-cell protein Tyrosine Phosphatase (TCPTP), play a crucial role in restricting the capacity of the IBD-associated inflammatory cytokine, interferon-gamma (IFN-γ) to induce barrier defects. This presentation will focus on the mechanisms by which TCPTP protects intestinal epithelial barrier function using knockout mouse models and novel epithelial cell lines lacking TCPTP or expressing mutated forms of PTPN2. This will include identification of specific epithelial tight junction molecular targets that are altered by TCPTP loss of activity, and approaches to restore a compromised epithelial barrier.

Cytokine-Mediated Regulation of Intestinal Inflammation: Beauty and the Beast
Tim Denning, PhD, Georgia State University

Several members of the IL-1 family of cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33) are up-regulated in the inflamed mucosa during experimental colitis and human IBD and polymorphisms in the some of these genes correlate with increased susceptibility to ulcerative colitis or Crohn's disease. Classic IL-1 family cytokines are produced predominantly by macrophages following inflammasome activation and caspase-1-mediated cleavage of a pro-domain and have potent pro-inflammatory functions. Once secreted, these IL-1 family members are involved in activation of innate and adaptive immune cells, and regulation of the intestinal epithelial barrier and permeability. Collectively, these observations suggest that IL-1 family members may contribute to intestinal inflammation during IBD. More recently, five additional IL-1 family members have been identified. IL-1F5 (renamed IL-36Ra), IL-1F6 (renamed IL-36α), IL-1F8 (renamed IL-36β) and IL-1F9 (renamed IL-36γ) all bind to the primary receptor IL-1Rrp2 (renamed IL-36R), which allows recruitment of the coreceptor IL-1RAcP, and the subsequent activation of the NF-kB and MAPK pathways. IL-36 receptor antagonist (IL-36Ra) blocks signaling by IL-36α, IL-36β, and IL-36γ through a mechanism similar to IL-1Ra inhibition of IL-1α and IL-1β. Thus, IL-36 signaling appears to be tightly controlled to limit excessive inflammation. The contributions of the IL-36/IL-36R axis during experimental and human IBD are just beginning to emerge and recent advances will be discussed.

Immune-mediated Regulation of Epithelial Damage and Regeneration within the GI Tract
Alan M. Hanash, MD, PhD, Memorial Sloan Kettering Cancer Center

Immune-mediated injury to the gastrointestinal (Gl) tract is an important cause of morbidity and mortality, and it is a frequent cause of toxicity after allogeneic hematopoietic transplantation. There is currently little understanding of how bone marrow transplant (BMT) recipients recover from tissue damage due to graft vs. host disease (GVHD), where donor T cells attack recipient epithelial tissues including the GI tract. There is also little understanding of how immune-mediated intestinal injury affects the intestinal stem cell (ISC) compartment. We have identified that Interleukin-22 (IL-22) is an important regulator of GI regeneration post-transplant and that IL-22 from ILCs directly stimulates ISC-dependent epithelial regeneration in vitro. After damage, ILCs are activated to produce IL-22, and crypt epithelial cells increase their expression of the IL-22 receptor. These findings support the idea that after intestinal damage the immune system is activated to contribute to the ISC niche in order to promote recovery of the tissue and restore the integrity of the mucosal barrier. However, this regenerative axis is disrupted in GVHD, as donor T cells lead to the elimination of IL-22-producing ILCs and loss of the IL-22-mediated regenerative response. We have also found that Lgr5+ ISCs, which are capable of regenerating all intestinal epithelial cells, are depleted in GVHD and that IL-22 deficiency exacerbates the loss of ISCs in GVHD. Therefore, tissue damage in GVHD may represent a "two-hit" process, where donor T cells attack the GI tract as well as the immune cells protecting it and promoting its recovery.

Microbial Metabolites that Modify Intestinal Wound Repair
Thaddeus Stappenbeck, MD, PhD, Washington University School of Medicine, Saint Louis

The timing and efficiency of wound repair in the intestine is influenced by the microbiome. Previous studies show that germ-free or antibiotic-treated mice have poor responses to mucosal damage. When injured, the mucosa undergoes repair in defined phases, all of which are influenced by the microbiome. The initial phase of repair is characterized by the covering a wound site by highly mobile, squamous epithelial cells. These cells, also known as wound associated epithelial cells (WAE) are produced by stem cells within crypts adjacent to the injury site. WAE cells undergo adaptive reprogramming under the influence of prostaglandin E2. Once the WAE layer begins to form, a second phase of repair commences that is characterized by an expansion of epithelial stem cells that also emanate from crypts that are adjacent to injuries. The expanded stem cells form channels within the wound bed that are directed towards the center of the injury. The wound bed mesenchyme is also highly organized and coordinated. Specifically, populations of mesenchymal stem cells and macrophages appear at specific times and locations within the wound bed and are required for repair. Microbial antigens and metabolites interact with specific cell types within the wound during specific phases of repair. We have found that specific microbial factors can either positively and negatively influence the rate and extent of repair after injury. These factors and the host pathways they engage have provided new insights into mechanisms of wound repair in the intestine.

Mucosal Barrier and Entero-hepatic Tissue Engineering
Linda Griffith, PhD, Massachusetts Institute of Technology

"Mice are not little people"—a refrain becoming louder as the strengths and weaknesses of animal models of human disease become more apparent. At the same time, three emerging approaches are headed toward integration: powerful systems biology analysis of cell–cell and intracellular signaling networks in patient-derived samples; 3D tissue engineered models of human organ systems, often made from stem cells; and micro-fluidic and meso-fluidic devices that enable living systems to be sustained, perturbed and analyzed for weeks in culture. This talk will highlight the integration of these rapidly moving fields to understand difficult clinical problems, with an emphasis on translating academic discoveries into practical use for analysis of mucosal barrier tissue function, inflammation, and entero-hepatic interactions. Specifically, approaches for building complex 3D mucosal barrier models using synthetic extracellular matrix, along with synergistic interactions between intercommunicating gut and liver will be described.
 
Coauthors: Kelly Chen¹, Victor Hernandez-Gordillo¹, Murat Cirit¹, Christi Cook¹, Jorge Valdez¹, Dave Trumper¹, Collin Edington¹, Gaurav Rohatgi², David Hughes³, and Doug Lauffenburger¹.
 
1. Massachusetts Institute of Technology
2. Continuum Innovations, Boston
3. CN Bioinnovations, London

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Directions to the Academy

Hotels Near 7 World Trade Center

Recommended partner hotel

Club Quarters, World Trade Center
140 Washington Street
New York, NY 10006
Phone: 212.577.1133

The New York Academy of Sciences is a member of the Club Quarters network, which offers significant savings on hotel reservations to member organizations. Located opposite Memorial Plaza on the south side of the World Trade Center, Club Quarters, World Trade Center is just a short walk to the Academy.

Use Club Quarters Reservation Password NYAS to reserve your discounted accommodations online.

Other nearby hotels