Tag Archives: Retinoid acid

The Dark Side of Retinoic Acid and Interleukin-22

Salmonella species growing on XLD agar - Showing H2S production
IL-22 secretion during intestinal inflammation gives Salmonella a competitive advantage.
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.


Th17 in the Human Gut and Bacteria Talk to Neurons

Unipolar Sensory Neuron
Bacteria can cause pain by interacting directly with neurons in the gut.
Crohn’s disease patients have more T helper 17-inducing lamina propria cells, bacteria activate pain neurons and retinoic acid determines the fate of pre-dendritic cells.

T helper 17 Cell Induction in the Human Gut

It’s easy to forget with the all the mouse immunology research that many things about gut Th17 cells haven’t been described with human cells. Now we are one step further. The journal Gastroenterology has an article in press that describes the induction of Th17 cells from human-derived, lamina propria cells. Using cells isolated from Crohn’s disease patient and control intestinal samples, Japanese scientists found an antigen-presenting cell population with a monocyte/macrophage lineage that was extremely good at inducing Th17 cells from naïve T cells. While both patient and control cells both could induce Th17, Crohn’s disease patient cells were the most effective. Th17 cells are suggested to play a role in Crohn’s disease, and this result supports this idea even more.

Bacteria and Nociceptors, Talking Together

Most of us have heard the term, “the second brain,” when people are referring to the neural networks within the intestinal system. Sensory neurons called nociceptors are responsible for the pain sensation. During intestinal Staphylococcus aureus infection, pain is induced, and, for a long time, it was assumed to be caused inflammatory mediators interacting with the pain neurons. Chiu et al, in the most recent issue of Nature, have now shown that, in actuality, it’s the bacteria that are directly activating the nociceptors. Furthermore, in neuron ablation experiments, they discovered that the nociceptors could influence inflammation. Interestingly, the communication wasn’t via pattern recognition receptors. Instead, the communication mediators were formylated peptides and α-haemolysis, a pore-forming toxin, produced by S. aureus. In the future, it will be interesting to find out how friendly commensals interact with nociceptors. They could form a novel way of modulating the immune response during intestinal inflammation.

Choosy Pre-Dendritic Cells Choose Retinoic Acid

Retinoic acid has a variety of effects within the gut-associated immune system, and it is known to influence the generation of different kinds of dendritic cells (DCs). However, it wasn’t known precisely when retinoic acid was having an effect on DC generation from pre-DCs or how it was affecting systemic DC populations. Scientists from the National Institute of Health now know the answer to both questions. They found that a retinoic acid deficiency caused a reduction in pre-DC-derived conventional DCs in both the spleen (CD11b+CD8α-Esamhigh DCs) and the gut (CD11b+CD103+ DCs), while populations of several other DC types were not affected. By transferring pre-DCs to different hosts with different retinoic acid levels, the scientists determined that ambient retinoic acid levels controls the fate of pre-DC. As conventional DCs are necessary for sufficient protective immune responses, this highlights the importance of vitamin A (precursor of retinoic acid) supplementation during mucosal stress.