Crohns Disease Treatment Also Helps Protect the Gut From Infection

Reading time: 4 – 6 minutes

The gene Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) encodes a cytokine, a signaling molecule secreted by immune cells that has an effect on other cells and is involved in inflammation. A recent report in Cell Host and Microbe reveals that in the gut, GM-CSF helps protect against infection by a bacterial pathogen [1].

GM-CSF has long been known to promote the survival and differentiation of dendritic cells, immune cells that are present in small quantities in tissues that are in contact with the external environment, including the skin and the inner lining of the nose, lungs, stomach and intestines. Dendritic cells are immune modulators that originate in the bone marrow and travel through the blood and lymph to the peripheral tissues in an immature state. Once they arrive, they differentiate and function as professional “antigen presenting cells”: they alert T cells and B cells to the presence of any foreign invaders. The T and B cells then mount an immune response.

Mice genetically engineered to lack GM-CSF (herein referred to as GM-CSF-/- mice) have normal numbers of dendritic cells, so GM-CSF is clearly not required for their maturation. However, these mice are particularly susceptible to respiratory infections. Because the intestinal tract is such a common entry portal for pathogens in mammals, Dr. Martin Kagnoff and his colleagues in the Department of Pediatrics at the University of California, San Diego (UCSD) decided to examine the role of GM-CSF in the gut.

They infected normal (wild-type) and GM-CSF-/- mice with Citrobacter rodentium, a mouse pathogen that is commonly used as a model for intestinal infections in humans. In the normal mice, the infection promoted increased GM-CSF production in the gut, but not in the spleen or lymph nodes. GM-CSF -/- mice were more susceptible to infection; they had lower serum titers of antibodies against the pathogen and took four weeks to clear the infection instead of the three weeks it took the normal mice. Before infection, both groups of mice had similar numbers of dendritic cells in their colons. But afterwards, the number of these cells increased significantly in normal but not GM-CSF-/- mice. In addition to being reduced in number, the dendritic cells in the mutant mice were deficient in endocytosis — the process by which they absorb the antigens they present. After infection, mice from whom these dendritic cells had been removed had more severe inflammation and lower antibody titers — just like the GM-CSF -/- mice. Thus, the researchers concluded that GM-CSF is important for mobilizing dendritic cells and regulating inflammation in an enteric infection.

Crohn’s disease is an autoimmune inflammatory bowel disease that usually affects the ileum, the lower part of the small intestine. The most common symptoms are abdominal pain and diarrhea, and complications often involve blockage of the intestine. GM-CSF provokes inflammation and exacerbates autoimmune diseases, so two therapies that decrease its production are widely used to combat inflammation in patients with Crohn’s disease.

Although it is entirely counterintuitive, administration of GM-CSF to these patients has been shown to reduce inflammation and improve their clinical profile [2]. However, an abnormal response to enteric bacteria is thought to contribute to pathogenesis of the disease. Dr. Kagnoff and colleagues suggest that the dendritic cells in people with Crohn’s disease cannot properly respond to microbial infection, and this explains why and how GM-CSF helps them. According to Kagnoff [3]:

The gut normally is in a chronic state of low-grade inflammation that is beneficial,” said Kagnoff. “This study shows that GM-CSF has a profound influence in the regulation of cells that determine whether the gut lives in peace with this inflammation, or becomes severely inflamed during infection. Any time that delicate balance is disrupted, all heck can break loose.

For more information on Crohn’s disease, see the Crohn’s & Colitis Foundation of America (CCFA), a non-profit, volunteer-driven organization dedicated to finding the cure for Crohn’s disease and ulcerative colitis.

References

1. Hirata et al. GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen. Cell Host Microbe. 2010 Feb 18;7(2):151-63.
   View Abstract
2. Dieckgraefe and Korzenik. Treatment of active Crohn’s disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet. 2002 Nov 9;360(9344):1478-80.
   View Abstract
3. Protein key to protecting the gut from infection. University of California press release. 2010 Feb 17.