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.
- Behnsen, J., Jellbauer, S., Wong, C. P., Edwards, R. A., George, M. D., Ouyang, W., & Raffatellu, M. (2014). The Cytokine IL-22 Promotes Pathogen Colonization by Suppressing Related Commensal Bacteria. Immunity, 1–12. doi:10.1016/j.immuni.2014.01.003
- O’Donnell, H., Pham, O. H., Li, L.-X., Atif, S. M., Lee, S.-J., Ravesloot, M. M., et al. (2014). Toll-like Receptor and Inflammasome Signals Converge to Amplify the Innate Bactericidal Capacity of T Helper 1 Cells. Immunity, 1–12. doi:10.1016/j.immuni.2013.12.013
- Sanders, T. J., McCarthy, N. E., Giles, E. M., Davidson, K. L. M., Haltalli, M. L. R., Hazell, S., et al. (2014). Increased Production of Retinoic Acid by Intestinal Macrophages Contributes to Their Inflammatory Phenotype in Patients with Crohn’s Disease. Gastroenterology, 1–61. doi:10.1053/j.gastro.2014.01.057