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.
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: 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.
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.