Macrophages Like IL-10 and DNA Methylation Regulates Tregs

This week on TIBDI, we see a plethora of interesting articles including a parallel publication about the necessity of IL-10 conditioning for gut macrophages and the ways that DNA methylation influences colon Treg proliferation.

IL10 Crystal Structure.rsh
IL-10 is an important conditioning factor for gut macrophages.
Intestinal Macrophages Need IL-10 Conditioning: Parallel Publication

Macrophages are an important immune cell of the intestines. For instance, CX3CR1hi macrophages capture antigens from the lumen by extending dendrites up through the epithelial layer and into the mucus to interact with passing bacteria. In the latest set of publications by the journal Immunity, parallel articles examine the relationship between macrophages and the anti-inflammatory cytokine interleukin (IL)-10. Using two different approaches, Dr. Ehud Zigmond of the Weizmann Institute of Science in Israel and Dr. Dror S. Shouval of Harvard Medical School in the United States were able to make similar conclusions.

Dr. Zigmond, using macrophage-restricted Il-10-/- and Il-10ra-/- mice, determined that macrophages with deficient IL-10 secretion were not nearly so harmful to the gut as macrophages not being able to respond to IL-10. Losing the ability to be conditioned by IL-10 made the macrophages more pro-inflammatory and led to spontaneous colitis. Dr. Shouval approached his research by creating bone-marrow chimeras with Rag2-/-Il-10rb-/- bone marrow and using the T cell transfer model of colitis. He found that loss of IL-10 signaling in innate immune cells led to colitis development. His work, unlike that of Dr. Zigmond, revealed that IL-10 conditioned macrophages are needed for proper regulatory T cell (Treg) development, and mucosal immune tolerance. He also found that pediatric inflammatory bowel disease (IBD) patients with mutations in their IL-10 receptors also had more pro-inflammatory macrophages. This work may lead to insights about why IBD develops.

Colonic Treg Proliferation Needs Uhrf1

Finding the ways that epigenetic mechanisms control T cell function and numbers is an exciting new field of research. One of the latest Nature Immunology articles adds fuel to the fire by publishing the work of Dr. Yuuki Obata of the University of Tokyo in Japan. She found that the DNA-methylation adaptor Uhrf1 was needed for Treg proliferation in the colon. This was determined by profiling genes activated in proliferating Treg after colonization with bacteria. This was then confirmed using T cell-specific Uhrf1-/- mice. Loss of Uhrf1 led to hypomethylation of a cell-cycle gene and a loss of Treg division in the colon. As a consequence of the low Treg numbers, Uhrf1-/- mice developed spontaneous colitis. It will be interesting to see if the same results can be found in the human setting.

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