Response to “Modification of cell fate by innate immunity: Role of epigenetic plasticity and epigenetic memory”

We thank Drs. Li and Hao for their thoughtful comments regarding our recent paper on the role of innate immunity in transdifferentiation of human fibroblasts to endothelial cells¹. They correctly state that the epigenetic landscape is different from one somatic cell to another, and that the determinants of that epigenetic landscape (such as small RNAs, transcriptional factors and chromatin modifiers) also differ from one somatic cell to another. Accordingly, they pose an excellent question: because of the known differences between somatic cells in their epigenetic landscape and regulation, what role does innate immune signaling may play in the transdifferentiation of other somatic cells? In the absence of direct experimental evidence, we believe that we have identified a common mechanism for epigenetic plasticity that is triggered by inflammatory signaling. We call this process transflammation².

It is likely that this process of transflammation occurs naturally. At sites of chronic inflammation, a change in phenotype of the resident cells is often observed. For example, with chronic esophagitis due to gastroesophageal reflux disease the stratified squamous esophageal epithelium transdifferentiates into a columnar epithelium resembling that of the small intestine³. This so-called Barret’s esophagus may later be the site of malignant transformation. Whereas chronic inflammation may be the site of pathological changes in cell phenotype, we believe that inflammatory signaling that is transient and physiological provides for therapeutic transdifferentiation. Indeed, it was recently reported that after experimental myocardial infarction, fibroblasts may transdifferentiate into endothelial cells, increasing microvascular density in response to the ischemic injury⁴.

Somatic cells detect pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) by means of pattern recognition receptors (PRRs) such as toll-like receptors⁵. Activation of PRRs triggers the generation and release of cytokines and chemokines that contribute to the inflammatory response. We have found that activation of PRRs also causes global changes in epigenetic modifiers that favors an open chromatin configuration. The resulting increase in epigenetic plasticity permits somatic cells to reach into their genetic toolbox to pull out what they need to adapt and survive. Further elucidation of the mechanisms of “transflammation” will permit its therapeutic modulation in the treatment of chronic diseases, infection and cancer.