Macrophage tolerance in the gut: It is in the epigenome!

Intestinal macrophages are functionally specialized to phagocytose bacteria, including harmful and invading pathogens, without releasing pro-inflammatory mediators. This unique functional combination guarantees an optimal defense against millions of gut bacteria while at the same time protecting the host from inflammation-related tissue damage. IL-10 seems to be a critical tissue factor involved in this balance and deficiencies in IL-10 in humans and mice have been shown to deteriorate this fine balance, leading to chronic inflammation and diseases such as Crohn's disease. However, the molecular mechanisms downstream of IL-10 are poorly understood. In this issue of European Journal of Immunology, Simon et al. [Eur. J. Immunol. 2016. 46: 1912-1925] demonstrate that the chromatin landscape in gut macrophages derived from mice lacking IL-10 is characteristic of inflammatory macrophages, even in the absence of bacteria. The observed changes of the chromatin landscape represent an important initiating event in chronic intestinal inflammation. These observations are not only an excellent example linking a classical loss-of-function experiment to a molecular mechanism responsible for the induction of chronic inflammation; they also open up new avenues for targeting chromatin and remodeling enzymes in Crohn's disease.