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.
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 on TIBDI: Impressive results in Nature show how gene mutations cause reduced autophagy, and mutations in the XIAP gene lead to early-onset CD in male patients.
From an Autophagy Gene to Crohn’s Disease
Genome wide association scans confirmed the importance of ATG16L1 mutations in Crohn’s disease (CD), especially a variant consisting of an Alanine to Threonine exchange at the 300th amino acid. Despite an abundance of literature, the precise mechanism linking the mutation to reduced autophagy was unknown. Dr. Aditya Murthy from Genentech, Inc. has now found an answer. The mutation is located in a cleavage site for the enzyme caspase-3, and it makes the protein more susceptible to cleavage. Caspase-3 is well known for its role in initiating apoptosis during cellular trauma, for instance during metabolic stress or intestinal infection. Without proper autophagy, macrophages are unable to neither regulate their energy consumption nor properly eliminate pathogens, and have an heightened inflammatory response.
XIAP Mutations in Early Onset CD
Variants in the gene encoding for the X-linked inhibitor of apoptosis protein (XIAP) can sometimes lead to intestinal inflammation. XIAP is involved with a multitude of processes including NOD signaling, apoptosis and NKT cell development. To investigate XIAP’s possible role in CD, Dr. Yvonne Zeissig and her colleagues at the University Medical Center Schleswig-Holstein in Germany, looked at CD patient samples to find if there were clear associations between XIAP and immune cell function. She found that approximately 4% of male early-onset CD patients had unique mutations in their XIAP genes. Experiments with patient primary cells revealed that loss of XIAP function caused defects in NOD1/2 signaling.
This week on TIBDI: Th1 cells can activate macrophages with innate signals alone, retinoic acid is no hero in Crohn’s disease, and interleukin-22 allows some pathogens to thrive.
TCRs Are Not Always Needed
Macrophages and T cells play are important in inflammatory bowel disease (IBD). Learning about how these cells interact could lead to more insight about how IBD progresses. Hope O’Donnell of the University of Minnesota has now gleaned new insights about their interactions. She looked into the mechanisms behind non-cognate stimulation of Th1 cells (non-TCR stimulation) and their ability to secrete macrophage-activating IFNγ. Using genetically manipulated mice and a Salmonella infection model, her results show that Th1 (and CD8+) cells produce plenty of IFNγ as long as they are exposed to Toll-like receptor ligands and products of activated inflammasomes like interleukin (IL)-18 and IL-33. This study underscores the flexibility and strength of the adaptive immune response.
The Pitfalls of Retinoic Acid
Retinoic acid is the current darling of those studying anti-inflammatory responses as it has been shown that retinoic acid can lead to regulatory T cell development. To determine if retinoic acid was actually lowered during Crohn’s disease (CD), Dr. Theodore J. Sanders of the Blizard Institute in London measured retinaldehyde dehydrogenase (RALDH) activity in cell samples collected from CD patients and controls. In all of the dendritic cells and macrophages tested, the RALDH activity (ability to produce retinoic acid) was increased in CD patients compared to controls. Surprisingly, blocking retinoic acid signaling actually decreased the ability of monocytes to differentiate into TNFα-producing macrophages in in vitro tests. This would suggest that retinoic acid is less helpful in CD than what one would expect.
Salmonella Exploits Interleukin-22
Interleukin-22 is a cytokine that is designed to boost immune defenses at the gut-lumen interface. It induces antimicrobial peptide release along with factors that sequester essential metal ions (like iron) that bacteria need to grow. Dr. Judith Behnsen of the University of California has now discovered that these processes can be exploited by certain pathogens, like Salmonella. She found that IL-22 deficient mice were much less susceptible to Salmonella overgrowth. The reason was that Salmonella has the ability to compensate for the loss of ambient metal ions, while this is not the situation for many commensals. This allows Salmonella to create for a rather large niche for itself, while IL-22-induced processes decimate the competition.
This week on TIBDI: Soluble CD83 may be a useful anti-inflammatory factor, bacterial proteomics reveals new Crohn’s disease biomarkers, and GATA3 is an important transcription factor for group 3 innate lymphoid cells.
Soluble CD83, the Anti-Inflammatory Molecule
In order to control signals of membrane-bound receptors, the body often employs soluble versions that act as ligand sponges, preventing signaling on the stationary, active molecule. This is also the case with the pro-inflammatory, co-stimulatory molecule CD83, which is expressed on activated dendritic cells as well as activated T and B cells. The researcher Jenny Eckhardt, located at the University Hospital Erlangen in Erlangen, Germany, realized that this process might be involved in controlling intestinal inflammation and sought more answers with her team. They found that administration of soluble CD83 prevented colitis in a mouse model of inflammatory bowel disease. This was associated with improvements in many inflammatory mediators. They also determined that the positive effects of soluble CD83 were induced by indoleamine 2,3-dioxygenase, which is known to have immunosuppressive properties.
Metaproteomics for Crohn’s Disease Monitoring
Catherine Juste of the French National Institute for Agricultural Research (INRA) has zeroed in on new molecular parameters for Crohn’s disease (CD), which may impact future diagnosis, monitoring and treatment. While many have focused on categorizing the intestinal microbiota signatures of CD patients, her team went one step further and looked at the microbial protein signature. They found that many proteins from Bacteroides species were over represented. Many of the over-expressed proteins were for the invasion and breaching of the mucosa. This unique method of looking at bacterial proteins could lead to new targets to help treat CD.
GATA3’s New Identity
GATA3 is a transcription factor most well known for its role in inducing T cell differentiation towards Th2. However, Nicolas Serafini of the Pasteur Institute and French Institute of Health and Medical Research (INSERM) has now found that GATA3 has many more uses including the induction of group 3 innate lymphoid cells (ILC3). ILC3 are essential for generating a wave of epithelial cell-activating IL-22 after intestinal bacteria infection. ILC3 are also characterized by the expression of the Th17-associated transcription factor RORγt. GATA3 was necessary for these cells during development, and their loss led to a reduced resistance against an intestinal bacterial pathogen.