Tag Archives: Inflammasomes

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.

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

 

NLRP3 Beats Bacteria and Anti-TNFα Needs No Help

Citrobacter freundii Gram stain
NLRP3 helps prevent intestinal colonisation of Citrobacter bacteria.
This week on TIBDI: we learn why NLRP3 polymorphisms are interesting for Crohn’s disease, and the combination treatment of anti-TNFα and methotrexate isn’t better than anti-TNFα alone.

Continue reading NLRP3 Beats Bacteria and Anti-TNFα Needs No Help

The Role of NLRP6 in Stress Induced Intestinal Inflammation

TIBDI blog post 14-01Many inflammatory bowel disease patients know that stress can complicate and worsen their symptoms. Even though this has been generally known for years, the study of the relationship between the gut and the brain is just now gaining popularity. In the most recent issue of Gastroenterology, we finally get a glimpse of how stress leads to intestinal inflammation.

The study, performed by American, Chinese and Taiwanese researchers, investigated the signals induced by stress that lead to inflammation in the small intestine. For this work, they used a stress-induced model of enteritis in mice. The mice were placed on a small platform surrounded by water for one hour each day, for a total of ten days. The resulting disease was characterized by intestinal damage, reduced weight gain and intestinal permeability. Although, IL-17 and IL-6 were found to be increased in the small intestine, there was also striking loss of IL-1β expression, which is what apparently first sparked their interest in inflammasomes.

Inflammasomes are large multi-protein complexes that are needed to activate a family of enzymes known as the caspases, which are involved in cell death and inflammation functions. One of the most well-known caspases is caspase-1. It’s needed to activate IL-1β, which is done by cleaving an inactive precursor of IL-1β. Interestingly, the inflammasomes belong to the (NOD)-like receptor (NLR) family, which many of you might realize also includes NOD2, a receptor that is highly associated with Crohn’s disease.

After some real-time PCR work, they found that the mRNA expression for Nlrp6 was considerably downregulated. They could also eliminate the pathology just by forcing the expression of NLRP6, further supporting its importance.

NLRP6 is an interesting NLR. Previous studies using Nlrp6-/- mice have shown that loss of this inflammasome in colonic epithelial cells disturbs the intestinal flora, which leads to an overgrowth of the bacterial family, Prevotellaceae and the candidate bacterial phylum, TM7. Both of these bacteria types are suspects in IBD, and the knockout mice also displayed a mild intestinal inflammation and extreme susceptibility to chemically induced forms of colitis.

However, other studies with the same knockouts hint that NLRP6 is even more complex. It also seems to have the potential to downregulate signaling via the pro-inflammatory factors NF-κB and ERK making the knockout inherently pro-inflammatory. Which might lead one to believe that the intestinal pathology is only caused by an overactive immune system. However, one most also remember that the microflora community that develops in the knockouts also can induce the same intestinal problems in wild type mice.

In my opinion, these conflicts could be a result of immunological compensation in the knockout. The knockout studies  emphasize the importance of this current study, which was performed in wild type mice and represents what can happen with a normal complement of genes.

The next question of the researchers was how did stress translate into the reduction of NLRP6. They looked at corticotropin-releasing hormone (CRH), an important stress signal in the brain-gut axis. They found that during stress the levels skyrocketed, and the levels were indirectly correlated with NLRP6 expression. More importantly, injecting mice with CRH was enough to mimic the pathology, and blocking it eliminated the stress-induced inflammation.

However, the previous study with the Nlrp6-/- mice indicated that the pathology was caused by the ultimate overgrowth of bad bacteria, which was transmissible by co-housing. Co-housing stressed mice with unstressed mice led to the development of intestinal problems in the unstressed mice. Simple probiotic therapy was enough to protect the co-housed unstressed mice. A detailed investigation of the bacterial populations in the intestines of the stressed mice showed that it, indeed, was changed, and both the small and large intestine had an increased bacterial load.

To sum it up, this study shows that stress can lead to increased CRH, which reduces NLRP6 expression. NLRP6 expression is important for the activation of IL-1β and IL-18. Both of these cytokines are important for the control of bacterial infection, and, thus, loss of NLRP6 could possibly lead to loss of control of bacterial growth. In this study, this appears to be the case, and mice with stress have a changed intestinal flora that, on its own, appears to cause intestinal inflammation in unstressed mice.

This study is intriguing. Could it be that many intestinal pathologies are caused by long-term stress that changes one’s intestinal microbiota? I think it could be the case. However, the chance that this causes inflammatory bowel disease by itself is highly unlikely. One mustn’t forget that there is still a genetic component to inflammatory bowel disease. Yet, it wouldn’t surprise me if it were discovered that those with inflammatory bowel disease have experienced more stress at critical periods in their lives than healthy individuals.

References

Anand, P. K., Malireddi, R. K. S., Lukens, J. R., Vogel, P., Bertin, J., Lamkanfi, M., & Kanneganti, T.-D. (2013). NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature, 488(7411), 389–393.

Elinav, E., Strowig, T., Kau, A. L., Henao-Mejia, J., Thaiss, C. A., Booth, C. J., et al. (2011). NLRP6 Inflammasome Regulates Colonic Microbial Ecologyand Risk for Colitis. Cell, 145(5), 745–757.

Kuehbacher, T., Rehman, A., Lepage, P., Hellmig, S., Folsch, U. R., Schreiber, S., & Ott, S. J. (2008). Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease. Journal of Medical Microbiology, 57(12), 1569–1576.

Sun, Y., Zhang, M., Chen, C. C., Gillilland, M., Sun, X., Zaatari, El, M., et al. (2013). Stress-Induced Corticotropin-Releasing Hormone-Mediated NLRP6 Inflammasome Inhibition and Transmissible Enteritis in Mice. Gastroenterology, 144(7), 1478–1487.e8.