This week on TIBDI: NOD2 and IFNγ work together to recruit cells to the small intestine, and a microRNA offers an interesting way to control Th17 differentiation.
NOD2 Behind Intestinal T Cell Recruitment
One of the most important receptors involved with Crohn’s disease (CD) is NOD2, a pattern recognition receptor that recognizes bacterial cell walls. Dr. Xingxin Wu of the Yale University School of Medicine investigated its involvement in an acute intestinal disease model induced by systemic anti-CD3. His results provide unique insight into infiltration dynamics of the characteristic CD8+ T cells found in the small intestine of this model. He discovered that NOD2 stimulation was needed for optimal infiltration. Without these signals, chemokines, specifically CXCR3-ligands, were not secreted by macrophages, dendritic cells and stromal cells. This prevented CD8+ T cells from leaving the circulation and entering the intestinal lamina propria. Moreover, the loss of CD8+ T cells in the small intestine led to reduced IFNγ, which also plays a role in stimulating immune cell chemotaxis.
Unexpected MicroRNA Control of Th17
During low oxygen conditions, immune cells upregulate transcription factors that turn on genes that help them cope with the hypoxia. One of these transcription factors, HIF-1α, also contributes to the differentiation of Th17 cells, which are important in the pathogenesis of inflammatory bowel disease (IBD). In an extremely interesting Nature Immunology publication, Dr. Haopeng Wang of the University of California in San Francisco described how the microRNA Mir210 inhibited HIF-1α expression and Th17 differentiation. MicroRNAs are small RNAs that prevent gene expression. By controlling the abundance of Mir210, he was also able to influence the numbers of Th17 T cells differentiated in vitro. Using the T cell transfer model of colitis with genetically manipulated T cells, which lacked Mir210 expression, he found that Mir210-deficient T cells caused increased numbers of Th17 and worsened symptoms. The authors suggest that drugs that function similarly to Mir210 could be interesting therapeutics.
Wang, H., Flach, H., Onizawa, M., Wei, L., McManus, M. T., & Weiss, A. (2014). Negative regulation of Hif1a expression and T. Nature Immunology, 1–10. doi:10.1038/ni.2846
Wu, X., Lahiri, A., Haines, G. K., Flavell, R. A., & Abraham, C. (2014). NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute Injury. The Journal of Immunology. doi:10.4049/jimmunol.1302436
This week we find new ways that bacteria interact with the gut, aluminum looks like a deadly suspect in inflammatory bowel disease and parasitic worms seem to have their own T helper subset.
Bacteria Escapism in Crohn’s Disease Revealed
Adherent-invasive Escherichia coli (AIEC) are found in Crohn’s disease (CD) patients and are able to aggravate inflammation. Control of these kinds of bacteria requires functional autophagy, which destroys intracellular pathogens. Researchers from the University of Auvergne in France have now discovered that AIEC protect themselves from destruction by manipulating the genes needed to control autophagy. This was achieved by an upregulation of microRNAs designed to inhibit ATG5 and ATG16L1 expression. Blocking the microRNAs restored autophagy and reduced inflammatory responses. This mainly in vitro study suggests that restoring autophagy in CD may lead to lowered inflammation.
Aluminum: New Culprit in Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) incidence has risen simultaneously with industrialization and the emergence of modern society. This suggests that environmental pollutants may cause IBD. One possible guilty suspect is aluminum, which is known to be associated with abnormal immune function. To determine if aluminum was involved with intestinal inflammation, scientists from France administered aluminum to three types of murine IBD models. They found that aluminum worsened disease severity in each model, impaired intestinal barrier function and directly increased cellular immune responses.
Parasitic Worms Get Their Own T Cell Subset
Parasitic worms are now being investigated in clinical trials as a possible way to treat IBD. Research investigating the immune response generated by parasitic worms would be helpful for refining these studies. A current publication in Immunity does just this by examining T cell responses and the clearance of Nippostrongylus brasiliensis, a worm similar to Necator americanus used in the mouse IBD studies. They found that interleukin-9 producing T cells (Th9) were essential for worm clearance and the induction of T helper 2 cytokines. An interesting research question would be to determine if Th9 is involved in the therapeutic effect of parasitic worms in IBD.
Pathogens Plunder the Gut after Antibiotic Treatment
Antibiotic treatment is associated with IBD development. In general, this is likely associated with the resultant changes in the microbiota and also the entrance of enteric pathogens. Finding ways to use antibiotics safely could prevent some cases of IBD. A research team from Stanford has brought us one step closer by clarifying how some enteric pathogens thrive after antibiotic treatment. They found that the availability of bacterial sugars after antibiotics is part of the problem. Normal microbiota “harvest” sugars attached to the mucus for food. However when antibiotics are applied, surviving Salmonella typhimurium and Clostridium difficile quickly utilize the free sugars to grow and thrive.
Deficient autophagy causes an increase of phagocytosis, micro-RNAs control autophagy genes in Crohn’s disease and surprising results after gut dendritic cell depletion.
Autophagy Mediates Phagocytosis
Mutations in genes involved in autophagy are often found in patients with Crohn’s disease (CD). Autophagy or “self eating” is the process that a cell uses to re-process its own organelles and proteins. It also is related to phagocytosis, the mechanism used by phagocytic cells to engulf particles in their direct environment. Autophagy helps direct the digestion of engulfed particles. Scientists from the Baylor College of Medicine asked themselves if deficiencies in autophagy could also be correlated with problems in phagocytosis. For this they used Atg7 deficient mice, which miss a key autophagy gene. They found that these mice had macrophages with exceptional phagocytic capacities. This was caused by an increase of scavenger receptor expression. During Mycobacteria infection, these mice also displayed worse symptoms due to the higher Mycobacteria loads in the macrophages.
Micro-RNA Mediated Loss of Autophagy in Crohn’s Disease
Micro-RNAs control gene expression by binding and blocking mRNAs needed for protein translation. Using human cell lines and CD patient colon tissues, researchers from the University of Alabama investigated if micro-RNAs were involved in the control of the gene ATG16L1, which is a known mutated autophagy gene in CD. By controlling the levels of two micro-RNAs, MIR106B and MIR93, they were able to influence the expression of ATG16L1, the formation of autophagosomes and the process of autophagy in an in vitro model of bacterial infection. An examination of CD colon tissue also found an unusual increase of MIR106B along with a decrease of ATG16L1, which would lead one to conclude that there could be reduced antibacterial activity in CD colons.
Gut Dendritic Cells: Modulate T Cells and Not Microflora
Using a complex transgenic mouse expressing human proteins in lamina propria dendritic cells (DCs), researchers from the University of Minnesota found they had the perfect model to specifically deplete CD103+CD11b+ DCs, known to be needed to generate crucial, antimicrobial T helper 17 (Th17) responses. Interestingly, the loss of these cells did not cause increased susceptibility to two well known, intestinal bacterial infections (Citrobacter and Salmonella). This is surprising as the normal generation Th17 cells was impaired in the DC deficient mice. These mice also had no changes in their microflora suggesting that the loss of DCs had no affect on bacterial populations in the gut. One caveat of this study is that they did not show the populations of Th17 cells during the bacterial infections.
Do you have an opinion about any of these findings? Please let us know in the comments below!