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.
- Bel, S., Elkis, Y., Elifantz, H., Koren, O., Ben-Hamo, R., Lerer-Goldshtein, T., et al. (2014). Reprogrammed and transmissible intestinal microbiota confer diminished susceptibility to induced colitis in TMF-/- mice. Proceedings of the National Academy of Sciences of the United States of America. doi:10.1073/pnas.1319114111
- Hoque, R., Farooq, A., Ghani, A., Gorelick, F., & Mehal, W. Z. (2014). Lactate Reduces Organ Injury in Toll-like Receptor- and Inflammasome-Mediated Inflammation via GPR81-mediated Suppression of Innate Immunity. Gastroenterology, 1–37. doi:10.1053/j.gastro.2014.03.014
- Shen, P., Roch, T., Lampropoulou, V., O’Connor, R. A., Stervbo, U., Hilgenberg, E., et al. (2015). IL-35-producing B cells are critical regulators ofimmunity during autoimmune and infectious diseases. Nature, 507(7492), 366–370. doi:10.1038