Category Archives: Receptors

Notch for Oral Tolerance and Integrin Targeting in Crohn’s Disease

This week on TIBDI! Notch signaling is needed for the development of antigen sampling macrophages, and blocking integrins on T cells leads to less migration and colitis.

Notch signaling appears to be necessary for the development of cells that sample luminal antigens.
Notch and Intestinal Antigen Samplers

Recent literature has brought to light that macrophage-like cells expressing the chemokine receptor CX3CR1 and the integrin CD11c are needed to continually survey the antigen contents of the intestinal lumen. However, very little was known about how these cells develop. In a new publication, Dr. Chieko Ishifune of The University of Tokushima Graduate School in Japan shows that Notch signaling is involved. The Notch family is a highly conserved set up receptors designed for local cell communication, and they are involved in immune cell development. Using targeted knock-out mice, the researchers found that the downstream transcriptional regulator Rbpj was necessary for CD11c+CX3CR1+cells. Moreover, Notch1 and Notch2 were also needed. These results will help scientists learn more about oral tolerance, which could play a role in IBD.

Integrin Targeting Supported for Crohn’s Disease

The integrin α4 is suspected to be important for the recruitment of T cells to intestinal tissues. This concept is supported by the success of two blocking antibodies, Natalizumab and Vedolizumab, in Crohn’s disease (CD) clinical trials. To precisely examine the role of integrins on T cells during colitis, Dr. Elvira Kurmaeva of Louisiana State University Health Sciences Center transferred CD4+ T cells with a targeted deletion of α4 or β1 to induce colitis in immunodeficient mice. Her results indicated that loss of α4β7 lowered colitis severity. Further analysis of the colons showed that the mice had lower amounts of infiltrating CD4+ T cells, which matched results found in CD patients treated with Natalizumab. Interestingly, the migration problems were only apparent during inflammation, and didn’t affect T cell polarization.



B Cells and Lactate Slow Down the Immune Response

Sodium lactate
A simple injection of sodium lactate can influence inflammasome activation.
This week on TIBDI: IL-35-secreting B cells inhibit immune responses; lactate interferes with inflammasome activation; and mucus and microbiota link nature and nurture.

New Inhibitory B Cells

B cells, known more for their antibody producing potential, also have a regulatory function when they secrete the anti-inflammatory cytokine interleukin (IL)-10. In a recent publication of Nature, Ping Shen and Toralf Roch of the German Rheumatology Research Center (DRFZ) in Germany discovered that IL-35-secreting B cells also play a similar role. They found that triggering co-stimulatory receptors on B cells induced IL-35 production and that IL-35-deficient B cells both hindered the recovery from a model of autoimmune disease (multiple sclerosis) and increased the immune response to an intestinal pathogen (Salmonella). Given the widespread influence of IL-35 producing B cells during infection and inflammatory disease, it will be interesting to see if they also are important for inflammatory bowel disease (IBD).

Lactate Slows Down Inflammasomes

Previous literature has indicated that the NLRP3 inflammasome is associated with Crohn’s disease (CD), and may be needed to induce protective immune responses against invading bacteria. Inflammasomes in macrophages are activated, in part, by danger signals. While danger signals mainly induce pro-inflammatory cytokine production, they also stimulate metabolic pathways, and one product that is produced is lactate. According to results produced by Rafaz Hoque of Yale University, lactate can function as a negative regulator of inflammasome activation. The team at Yale found that stimulation of the lactate receptor GPR81 could modify Toll-like receptor 4 signaling and lower subsequent NLRP3 activation. In vivo, lactate was effective at reducing acute organ injury in models with potent inflammasome activation, such as hepatitis and pancreatitis. This could mean that lactate modulates NLRP3 responses in Crohn’s disease as well.

Nature, Nurture and Mucus Production

Intestinal mucus has the important function of preventing bacterial contact with the epithelial surface. In fact, TMF-/- mice lacking a specific Golgi-associated protein (TMF/ARA160), which produce thick mucus, are generally protected from experimental colitis. However, Shai Bel of the Bar Ilan University in Israel has found that the protection is not derived from mucus alone. The intestinal microbiota are also important. The team found that the microbiota of TMF-/- mice is different from that of wild-types, and has larger populations of bacteria from the Firmicutes phylum. Even more importantly, transfer of these populations to normal mice, by co-housing, also transferred the colitis protection. This underscores the potential role of microbiota manipulation in lowering IBD susceptibility despite genetic predisposition.

Q: What’s your opinion about microbiota manipulation for IBD prevention? Feel free to contribute your thoughts here or on the LinkedIn discussion group.


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

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.


Ulcerative Colitis’ NKT Cells and Nanoparticle siRNA

Nanoparticles may be a new way to transport active molecules to specific cells in IBD patients.
This week on TIBDI: Interleukin-13-producing NKT cells may be behind ulcerative colitis, and nanoparticle transport of CD98 small interfering RNAs may offer new treatment options for IBD.

An NKT Cell Antigen for Ulcerative Colitis

Ulcerative colitis (UC) is well known for its association with Th2 responses. More recently, it was found that IL-13-producing, Type II NKT cells accumulate in a rodent model of UC. Furthermore, these studies showed that IL-13 is cytotoxic for the epithelial cells and increases the killing activities of NKT cells. Dr. Ivan J Fuss of the National Institutes of Health continued this work in human UC patients. He found that the NKT cells accumulate in the lamina propria and when exposed to the self-antigen lyso-sulfate begin to secrete large amounts of IL-13 and upregulate IL-13Rα2 (IL-13 receptor). The authors speculate that these cells could be the main drivers of UC inflammation and that a key pathologic event in UC may be the abnormal expression of lyso-sulfate by gut epithelial cells in response to signals from microbiota.

Nanoparticles for the Treatment of IBD

Small interfering RNAs (siRNAs) offer the possibility of treating IBD by silencing disease-related genes. However, carriers are needed to bring these molecules to the cytoplasm of the correct cells. Dr. Bo Xiao of Georgia State University found success delivering CD98 siRNA to CD98+ gut cells by using orally administered nanoparticles coated with a targeting antibody and polyethylene glycol, which allows the particles to enter the mucus layer and reach the immune cells below. CD98 is part of the amino acid transporter LAT1, which amplifies integrin signaling and supports immune cell activation. The research team was able to successfully use their system to reduce the symptoms of two colitis models.


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.