Tag Archives: IL-10

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.

References

Regulatory T cell Development and Crohn’s Disease Siblings

Albert Anker Schreibender Knabe mit Schwesterchen I 1875
Siblings of Crohn’s disease patients have signs of inflammation.
This week on TIBDI: A gene behind very early onset inflammatory bowel disease (IBD) is uncovered, the receptor needed for colon regulatory T cell development is found and siblings of Crohn’s disease (CD) patients have signs of nascent intestinal inflammation.

Gene Behind Early Onset IBD

While many IBD cases are diagnosed during young adulthood and middle age, there is subset of patients that develop the disease before the age of six. To determine if there were certain mutated genes behind this early disease presentation, scientists from a multitude of institutions examined the DNA of children with very early onset IBD. They found that the children had loss of function mutations in the gene for tetratricopeptide repeat domain 7 (TTC7A). TTC7A is involved with phosphatidylinositol-4 kinase signaling. When the researchers specifically knocked down this gene in intestinal cell lines, they found that the cells lost adhesion and had increased apoptosis. This supported the clinical presentation in the children studied, which was marked by apoptotic enterocolitis.

Regulatory T cell development with GPR109A

Butyrate, a short chain fatty acid (SCFA) produced by intestinal bacteria, was recently shown to induce regulatory T cells in the colon. Scientists from Georgia Regents University have now clarified this effect even further by discovering the butyrate receptor behind increased regulatory T cells. This receptor is GPR109A, and it is also the receptor for the B vitamin niacin. They found that both butyrate and niacin gave anti-inflammatory properties to dendritic cells and macrophages via GPR109A, which encouraged Foxp3 and IL-10 expression in T cells. In colitis models, loss of the receptor led to severe disease. Studies using germ-free mice suggested that regulatory T cell defects caused by the loss of microbiota-derived butyrate could potentially be replaced by pharmacological doses of niacin.

CD Siblings As CD Models

Sisters and brothers of CD patients have an increased risk of developing disease. Initial studies of these potential patients show that they have some signs of intestinal inflammation like increased fecal calprotectin and intestinal permeability. Scientists from the United Kingdom have now investigated further and found that CD patients and their siblings have other striking similarities, such as abnormal changes in the intestinal microbiota and T cell phenotypes. The siblings were significantly different from control healthy populations, making them an unique “at risk” group. The researchers feel that studies of patient siblings could lead to new insights about the immune processes that lead to full blown CD.

References

Macrophages Encourage Autophagy and Are Hindered by IL-10

Macrophage
Macrophages could play a key role in the initiation of IBD.
This week on TIBDI: Macrophages are reined in via their IL-10 receptors, Macrophage derived Wnt1 encourages epithelial autophagy, and γδ T cells are controlled by BTLA and IL-7.

Continue reading Macrophages Encourage Autophagy and Are Hindered by IL-10

Helminths and Peritoneal B Cells Reduce Colitis

Heligmosomoides
Heligmosomoides polygyrus bakeri. This murine intestinal parasite induces colon regulatory T cells.
This week reveals two interesting inflammatory bowel disease-related studies published in the Journal of Immunology. One shows how parasites can induce potent colon regulatory T cells, and the other describes the importance of peritoneal B cells in regulating inflamed intestines. For both articles, interleukin-10 plays a critical role.

Helminth Infections Induce Colon Protective Regulatory T Cells

Helminths have the ability to reduce harmful inflammation, and they are now being tested as therapeutic agents for inflammatory bowel disease in clinical trials. Using a helminth found in mice, Heligmosomoides polygyrus bakeri, scientists from Tufts attempted to learn how these parasites performed their function in the intestines. They found that the helminths increased the number of Foxp3+ regulatory T cells in the colons of host mice and increased their expression of interleukin-10 (IL-10). These regulatory T cells were capable of preventing experimental colitis in an IL-10 dependent manner.

IL-10 Expressing B Cells in the Peritoneal Cavity Modulate Colitis

B cells come in many types and are present at many locations of the body. Within the main abdominal cavity, called the peritoneal cavity, many types of B cells are found, including IL-10 producing ones called B10 cells. Scientists from Duke found that these B cells also play an important role in colitis by lowering the severity of the inflammation. The production of IL-10 by these B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, Th1 cells, and proinflammatory cytokine production.

Do you think that interleukin-10 is the über-cytokine needed to control inflammatory bowel disease? Let us know in the comments below!

References

Hang L, Blum AM, Setiawan T, Urban JP Jr, Stoyanoff KM, Weinstock JV. Heligmosomoides polygyrus bakeri Infection Activates Colonic Foxp3+ T Cells Enhancing Their Capacity To Prevent Colitis. J Immunol. 2013 Aug 15;191(4):1927-34. doi: 10.4049/jimmunol.1201457. Epub 2013 Jul 12.

Maseda D, Candando KM, Smith SH, Kalampokis I, Weaver CT, Plevy SE, Poe JC, Tedder TF. Peritoneal Cavity Regulatory B Cells (B10 Cells) Modulate IFN-γ+CD4+ T Cell Numbers during Colitis Development in Mice. J Immunol. 2013 Aug 5. [Epub ahead of print]