Creeping Fat in Crohn’s Disease Leads to Creeping Dendritic Cells

Creeping fat is a form of mesenteric fat that's found in Crohn's disease patients.
Creeping fat is a form of mesenteric fat that’s found in Crohn’s disease patients.

An article in Mucosal Immunology shows that the creeping fat factor, leptin, can cause dendritic cells to become more migratory in Crohn’s disease. Could this be the key to disease progression?

Visit my recent post to learn more about creeping fat.

For this post, there was certainly no lack of interesting options. The journal, Science, just posted an article on the long-term stability of gut microbiota and an article looking at the way that microbiota control regulatory T cell populations. Immunity hosted an article about RORγt innate lymphoid cells and three additional articles about how microbiota interact with and modulate the immune system. I appreciate all of the press that microbiota are now getting, but after my last post and the whole Nature Immunology series on microbiota, it’s time to think of something else. Mucosal Immunology had something different and interesting. In an article by Al-Hassi et al., is a story about Crohn’s disease, fat and dendritic cell migration.

Dendritic cells (DCs) are the scouts of the immune system. They hide out in the peripheral regions of the body, detecting and collecting information on invaders. Once they have collected this information, they become activated and travel to local lymph nodes and alert T cells. This activation process includes the expression of receptors that allow them to detect the signals produced by lymph nodes. C-C motif chemokine receptor 7 (CCR7) is the most important of these receptors, and it recognizes three different ligands produced by lymph nodes and the lymphatic endothelia: CCL19 and two variants of CCL21.

Al-Hassi et al. noted that in Crohn’s disease (CD), there is an increase of mesenteric fat that surrounds the inflamed intestines. This fat is called “creeping fat,” and its adipocytes secrete large amounts of inflammatory mediators, including a mediator called leptin. Leptin is well-known for its ability to modulate DC behavior and encourage a T helper type 1 (Th1) response via leptin receptors (LepRs). Furthermore, leptin encourages the expression of CCR7 on DCs and prolongs their lifespan. The researchers hypothesized that creeping fat via leptin could control DC responses in CD, increasing their ability to travel to local lymph nodes and initiate pro-inflammatory responses.

They first looked at the expression of CCR7 and LepRb on DCs isolated from the colons of healthy individuals. LepRb distinguishes itself from other LepRs by being the only one that can activate the transcription factor, STAT3, which is important for initiating pro-inflammatory gene expression and preventing apoptosis. They found that DCs isolated from the small intestine of healthy individuals expressed both these receptors, but not DCs from the colon. However, in the CD patient DCs, this was different. DCs from CD colons also expressed the receptors too.

Looking at the maturation status between DCs collected from both healthy and patient intestinal samples. They found no real difference indicating that the increased expression of CCR7 and LepRb was not related to the activation status of the DCs themselves. They then performed experiments of a more mechanistic nature, by exposing colon DC from healthy donors to leptin. They found that this led to extensive CCR7 expression (10% to 60%) and the migratory capacity was also sharply increased towards CCL19.

To give the same experiment a more physiological swing, they collected culture supernatant from CD biopsies and added this to isolated, healthy colonic DCs. This also caused the upregulation of CCR7, and the addition of a LepR blocking antibody eliminated the effect, indicating that the likely factor controlling the CCR7 upregulation was the leptin secreted into the supernatant from the CD biopsies.

Although this is a small study, it has a strong message, and one that will probably lead to even more exciting studies. In the discussion, they consider that the difference of expression between small and large intestinal DC may have something to do with increased traffic for the transport of self-antigen to lymph nodes to perpetrate oral tolerance in local T cell populations, which could very well be true. Furthermore, they note that creeping fat does appear early in CD giving it an even better chance to affect CD progression in the long-term.

However, Gut published an article about macrophage populations in creeping fat in June. These researchers found that mediators secreted by the creeping fat adipocytes actually encouraged the M2 macrophage type, which is associated with IL-10 production and an anti-inflammatory function. They speculated that this would indicate a protective role for creeping fat in CD, not a story that fits with the ideas of Al-Hassi et al.

Which leaves us with a lot of questions. While I am convinced of the good intentions of the macrophages in the aforementioned study, I am not convinced about the innocence of the creeping fat. Adipocytes of creeping fat produce many more pro-inflammatory factors besides leptin, and TNFα is one of them. My opinion is that the anti-inflammatory nature of the creeping fat macrophages is more a response to being bathed consistently with pro-inflammatory factors. Their response would then be somewhat similar to the myeloid suppressor cell phenomenon.

Experiments need to be done that look at how dangerous leptin-exposed, CCR7+ DC are in CD patients and examine the real role of creeping fat. Is it the initiator, a propagator or protector in CD?

Thanks for reading. Please let me know what you think about creeping fat in IBD! If you need a bit more background in immunology, visit my basic immunology page.

References:

Al-Hassi, H. O., Bernardo, D., Murugananthan, A. U., Mann, E. R., English, N. R., Jones, A., et al. (2012). A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn’s disease. Mucosal Immunology, 6(4), 751–761. doi:10.1038/mi.2012.113

Fink, C., Karagiannides, I., Bakirtzi, K., & Pothoulakis, C. (2012). Adipose Tissue and Inflammatory Bowel Disease Pathogenesis. Inflammatory Bowel Diseases, 18(8), 1550–1557. doi:10.1002/ibd.22893

Kredel, L. I., Batra, A., Stroh, T., Kuhl, A. A., Zeitz, M., Erben, U., & Siegmund, B. (2013). Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut, 62(6), 852–862. doi:10.1136/gutjnl-2011-301424

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