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.
This week we find new ways that bacteria interact with the gut, aluminum looks like a deadly suspect in inflammatory bowel disease and parasitic worms seem to have their own T helper subset.
Bacteria Escapism in Crohn’s Disease Revealed
Adherent-invasive Escherichia coli (AIEC) are found in Crohn’s disease (CD) patients and are able to aggravate inflammation. Control of these kinds of bacteria requires functional autophagy, which destroys intracellular pathogens. Researchers from the University of Auvergne in France have now discovered that AIEC protect themselves from destruction by manipulating the genes needed to control autophagy. This was achieved by an upregulation of microRNAs designed to inhibit ATG5 and ATG16L1 expression. Blocking the microRNAs restored autophagy and reduced inflammatory responses. This mainly in vitro study suggests that restoring autophagy in CD may lead to lowered inflammation.
Aluminum: New Culprit in Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) incidence has risen simultaneously with industrialization and the emergence of modern society. This suggests that environmental pollutants may cause IBD. One possible guilty suspect is aluminum, which is known to be associated with abnormal immune function. To determine if aluminum was involved with intestinal inflammation, scientists from France administered aluminum to three types of murine IBD models. They found that aluminum worsened disease severity in each model, impaired intestinal barrier function and directly increased cellular immune responses.
Parasitic Worms Get Their Own T Cell Subset
Parasitic worms are now being investigated in clinical trials as a possible way to treat IBD. Research investigating the immune response generated by parasitic worms would be helpful for refining these studies. A current publication in Immunity does just this by examining T cell responses and the clearance of Nippostrongylus brasiliensis, a worm similar to Necator americanus used in the mouse IBD studies. They found that interleukin-9 producing T cells (Th9) were essential for worm clearance and the induction of T helper 2 cytokines. An interesting research question would be to determine if Th9 is involved in the therapeutic effect of parasitic worms in IBD.
Pathogens Plunder the Gut after Antibiotic Treatment
Antibiotic treatment is associated with IBD development. In general, this is likely associated with the resultant changes in the microbiota and also the entrance of enteric pathogens. Finding ways to use antibiotics safely could prevent some cases of IBD. A research team from Stanford has brought us one step closer by clarifying how some enteric pathogens thrive after antibiotic treatment. They found that the availability of bacterial sugars after antibiotics is part of the problem. Normal microbiota “harvest” sugars attached to the mucus for food. However when antibiotics are applied, surviving Salmonella typhimurium and Clostridium difficile quickly utilize the free sugars to grow and thrive.