In the last post, we discussed a bit about how some stem cells are able foster memory T cells, which contribute to the chronicity of colitis. This time, I look at an article that sheds even more light on the role of the bone marrow during inflammation. It was found that under conditions of inflammation, stem cell number increase. During colitis, these cells proliferate and, ultimately, produce more neutrophils and macrophages.
- Hematopoietic stem cells and progenitor cells can be found outside the bone marrow during inflammation in the colon.
- This appeared to be mediated by T cell-derived cytokines.
- This process increased the amounts neutrophils and macrophages at the sites of inflammation.
Take home message: In light of my last post, T cells can profoundly influence the innate immune system through stem cells. This strengths their potential role in chronic inflammation.
Neutrophils and macrophages are directly involved in causing damage in the colon during inflammation. Neutrophils and macrophages are the tanks of the immune system and each has their own weapon. Neutrophils are capable of releasing granules containing harmful reactive oxygen species and enzymes. They also release microbial webs (à la Spiderman). Macrophages engulf harmful bacteria and other pathogens and then secrete cytokines (chemical messengers) that alert other immune cells.
The authors used mainly the T cell transfer colitis model, induced by transferring CD4+CD25-CD45RBhi T cells (naïve T cells) to Rag1-/- mice (mice lacking T cells). They found that the inflammatory environment created by T cell transfer colitis had an effect on hematopoietic stem cells (HSC) in the bone marrow (BM), causing them to proliferate. HSC are the stem cells that produce immune cells. The developmental process involves first the production of multipotent progenitor cells. These HSC daughters have a limited life span, but are capable of further differentiating into two types of progenitors, the myeloerythroid progenitors (CMPs) or common lymphoid progenitors (CLPs). CMPs can further differentiate into either megakaryocyte-erythroid progenitors (MEPs) or granulocyte-monocyte progenitors (GMPs). The authors found that under conditions of inflammation, the GMPs would begin to dominate the total myeloid progenitor population. Moreover, HSC and GMP were also found outside of the bone marrow in the spleen and even in the inflamed colon.
IFNg and GM-CSF were considered possible candidates for the induction of these changes. IFNg is produced mainly by T cells and is important in supporting a Th1-associated immunity and is also known to directly affect HSC function. When the authors neutralized IFNg in vivo with antibodies, they found that the proliferation of the HSC decreased considerably. GM-CSF, on the other hand, is produced by stromal cells in the bone marrow (e.g. fibroblasts) and can also be produced by Th17 cells. GM-CSF is known to be involved with the differentiation of granulocytes. When this cytokine was neutralized, there was little effect on the HSCs, but instead an effect of the downstream GMPs. They were less dominant and loss of GM-CSF reduced their ability to populate the spleen and the colon during colitis.
One point that the authors wished to make was that IL-23 was involved in their findings. This is because IL-23 has such a prominent role in IBD pathogenesis. Current studies looking at genetic association in IBD show that many genes involved in IBD have something to do with the IL-23 pathway. To make this point, they emphasized that in the T cell transfer model many of the transferred T cells eventually differentiate into Th17 cells that require IL-23 for maintenance. They also looked at a form of colitis induced by H. hepaticus infection of 129SvEv.Rag2-/- mice (mice lacking T cells) that is mediated via IL-23. They found that this model also displayed inflammation-associated changes in HSCs; abundant and proliferating HSCs were evident and neutralizing IFNg reversed the phenotype. They also looked at T cells isolated from both wildtype and IL-23R-/- mice and found that Th17-derived GM-CSF was at least partially dependent on IL-23R expression on T cells. However, the most convincing evidence was that IL-23-/- mice with T cell transfer colitis showed reduced GMP accumulations.
I find the IL-23 point in this article not particularly exciting. What I do like is the concept of T cell-derived GM-CSF and IFNg being so important in encouraging the production of excess GMPs during inflammation, though the authors didn’t actually prove this. Still, if you consider these findings together with my last post, which discussed how IL-7 is necessary for T cell transfer colitis by creating a niche for colitogenic memory T cells, it would almost seem that the MSCs (via IL-7) of the bone marrow are controlling inflammation by supporting memory T cells that can provide crucial information to the HSCs. The T cells “communicate” to the HSCs via IFNg that supports of HSC proliferation and mobilization to peripheral regions. GM-CSF would then provide an additional signal to encourage the differentiation of GMPs and, ultimately, the increase of neutrophils and monocytes.
In light of the last post, it seems that there is an intimate relationship between the stem cells of the bone marrow and T cells during colitis development. Naturally, the question is, which cells are more important in generating inflammation in the colon, the T cells or the stem cells? In other words, which cell really does rule them all?
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.
Griseri T, McKenzie BS, Schiering C, Powrie F. Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation. Immunity. 2012 Dec 14;37(6):1116-29. doi: 10.1016/j.immuni.2012.08.025. Epub 2012 Nov 29.