Category Archives: Colitis models

Macrophages Like IL-10 and DNA Methylation Regulates Tregs

This week on TIBDI, we see a plethora of interesting articles including a parallel publication about the necessity of IL-10 conditioning for gut macrophages and the ways that DNA methylation influences colon Treg proliferation.

IL10 Crystal Structure.rsh
IL-10 is an important conditioning factor for gut macrophages.
Intestinal Macrophages Need IL-10 Conditioning: Parallel Publication

Macrophages are an important immune cell of the intestines. For instance, CX3CR1hi macrophages capture antigens from the lumen by extending dendrites up through the epithelial layer and into the mucus to interact with passing bacteria. In the latest set of publications by the journal Immunity, parallel articles examine the relationship between macrophages and the anti-inflammatory cytokine interleukin (IL)-10. Using two different approaches, Dr. Ehud Zigmond of the Weizmann Institute of Science in Israel and Dr. Dror S. Shouval of Harvard Medical School in the United States were able to make similar conclusions.

Dr. Zigmond, using macrophage-restricted Il-10-/- and Il-10ra-/- mice, determined that macrophages with deficient IL-10 secretion were not nearly so harmful to the gut as macrophages not being able to respond to IL-10. Losing the ability to be conditioned by IL-10 made the macrophages more pro-inflammatory and led to spontaneous colitis. Dr. Shouval approached his research by creating bone-marrow chimeras with Rag2-/-Il-10rb-/- bone marrow and using the T cell transfer model of colitis. He found that loss of IL-10 signaling in innate immune cells led to colitis development. His work, unlike that of Dr. Zigmond, revealed that IL-10 conditioned macrophages are needed for proper regulatory T cell (Treg) development, and mucosal immune tolerance. He also found that pediatric inflammatory bowel disease (IBD) patients with mutations in their IL-10 receptors also had more pro-inflammatory macrophages. This work may lead to insights about why IBD develops.

Colonic Treg Proliferation Needs Uhrf1

Finding the ways that epigenetic mechanisms control T cell function and numbers is an exciting new field of research. One of the latest Nature Immunology articles adds fuel to the fire by publishing the work of Dr. Yuuki Obata of the University of Tokyo in Japan. She found that the DNA-methylation adaptor Uhrf1 was needed for Treg proliferation in the colon. This was determined by profiling genes activated in proliferating Treg after colonization with bacteria. This was then confirmed using T cell-specific Uhrf1-/- mice. Loss of Uhrf1 led to hypomethylation of a cell-cycle gene and a loss of Treg division in the colon. As a consequence of the low Treg numbers, Uhrf1-/- mice developed spontaneous colitis. It will be interesting to see if the same results can be found in the human setting.

References

The Crohn’s Disease Gender Bias and Neutrophils Disrupt the Gut

Neutrophils
Neutrophils (with purple irregular nuclei) can shed proteins that disrupt the intestinal barrier.
This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.

Neutrophils Bust Up the Intestinal Barrier

During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.

Why Crohn’s Disease Prefers Women

There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.

More Ways to Induce Anti-inflammatory Dendritic Cells

CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.

References

New Insights about NOD2 and Th17 Differentiation

microRNA Mir210
This little piece of RNA has the power to influence Th17 differentiation.
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.

References

  • 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

SIRT1 and Stress Suppress Regulatory T Cells

High traffic
Is it actually our stressful lives that are setting the stage for inflammatory bowel disease?
This week on TIBDI: Human stem cell transplantation redefines T cell repertoires, SIRT1 blocks the development of induced regulatory T cells, and stress sets the stage for intestinal inflammation.

Stem Cell Transplantation Wipes CD4+ T cell Memory

Human stem cell transplantation (HSCT) is a potential treatment for severe cases of inflammatory bowel disease (IBD). One way that HSCT works is by resetting the adaptive immune system. However, few studies have looked in depth at changes in the T cell repertoires. Dr. Paolo Muraro from the Imperial College of London has now addressed this question. In a HSCT trial for multiple sclerosis (MS) patients, he and his team used high-throughput sequencing to assess T cell receptor changes in 24 patients. They found that CD4+ and CD8+ T cells responded differently to HSCT. The patients’ CD4+ T cells were redefined and had a new repertoire of clones, while the CD8+ T cells reflected pre-HSCT clones. Resetting CD4+ T cells could be one reason why that HSCT is also successful for IBD.

SIRT1 Suppresses Suppressor Induction

Regulatory T cells (Tregs) are known to be important in IBD, and work from animal models shows that they can regulate the severity of symptoms. Previous work by Dr. Tatiana Akimova and her colleagues at the Children’s Hospital of Philadelphia demonstrated a connection between SIRT1 and Tregs. To investigate this more in induced Tregs, they used SIRT1 deficient cells in the T cell transfer model of colitis. Loss of SIRT1 increased the induction of Tregs and effectively attenuated colitis development. This result was mirrored in dextran sodium sulfate colitis using an inhibitor of SIRT1 (EX-527). It will be interesting in the future to see if targeting SIRT1 will work in a therapeutic setting.

Stress Hinders Regulatory T Cells

Most IBD patients are quite aware that stress plays a role in their disease progression. However, the connection between stress and IBD remains shaky. Dr. Wei Wu of Tongji University considered that the missing link could be Treg function. To test this concept, they stressed mice and investigated the Tregs both in vitro and in vivo. Tregs from stressed mice were unable to function as normal, and some expressed IL-17 and TNFα. Prolactin, a stress mediator, mediated this change via dendritic cells. Stressed mice were highly susceptible to colitis, however, blocking prolactin reduced colitis. The authors feel that stress and prolactin set the stage for IBD development by the conversion of Tregs from effective suppressors to harmful pro-inflammatory T cells.

References

Lost Faecalibacteria in IBD and IL-10 Influences Inflammasomes

Lab mouse
Mice deficient in IL-10 have over active inflammasomes, which cause colitis.
This week on TIBDI: A new review is published on the gut microbiome, IBD patients have less butyrate-producing bacteria, and IL-10 deficient mice are inflamed by inflammasomes.

Healthy Gut Microbiome in the Spotlight

The state of the intestinal microbiome, in essence the microbiota genome, is proving to be an important factor during disease development and progression. However before in depth studies are done to define disease-related microbiome profiles, it’s essential to also have an idea of what profiles define a healthy state. Dr. Emily B. Hollister of the Baylor College of Medicine and Texas Children’s Hospital reviewed the current literature. In general, the gut microbiome has approximately more than 10 million non-redundant genes, and a more diverse microbiome is healthier than less diverse one. Not everyone has the same types of populations of bacteria; most healthy microbiomes can be classified into three basic enterotypes. The influence of the microbiome extends to the immune system, cellular nutrition, cellular protection, metabolic processes and the functioning of the nervous system.

Lost Faecalibacteria in IBD

Many researchers are searching for the right probiotics to treat inflammatory bowel disease (IBD). To support this kind of search, simultaneous research investigating the microbiota in IBD patients as compared to healthy ones is also necessary. Wei Wang of Wuhan University recently published evidence that some major changes in the IBD microbiota are an increase in Bifidobacteria and Lactobacilli along with a loss of Faecalibacterium prausnitzii. The loss of F. prausnitzii was especially considerable in patients with active Crohn’s disease (CD). F. prausnitzii is known to produce butyrate, which is especially important for the formation of regulatory T cells in the colon. The author suggests that instead of focusing on common lactic acid producing probiotics in IBD, patients may be better served by looking at butyrate-producing probiotic species.

IL-10 Deficient Mice Inflamed by Inflammasomes

An interesting model of IBD is the interleukin (IL)-10 deficient mouse, which develops spontaneous colitis. Dr. J. Zhang of the Medical University of South Carolina found evidence that inflammasomes play a role in this model by promoting chronic intestinal inflammation. He found that loss of IL-10 increased the levels of NLRP3 and contributed to more inflammasome activity. This caused higher amounts of active IL-1β to be produced in gut tissues, which also led to increased colitogenic Th17. Blocking inflammsome activation successfully improved the colitis of the IL-10 deficient mice, suggesting that similar strategies could be useful in IBD.

References