Biology of embryo-derived Kupffer cells

Abstract

Kupffer cells (KCs) are the resident macrophages of the liver, and play a key role in innate immune sensing, and maintaining steady state. KCs are originated from embryonic precursors, or from bone marrow monocytes. In adult unmanipulated mouse liver, at least a subset of KCs are embryo-derived; thus the adult liver KC compartment shows ontogenetic heterogeneity. Liver injury models of pathogenic and sterile inflammation indicate functional heterogeneity of KCs, and they can be pro-inflammatory, anti-inflammatory, immunosuppressive, or reparative. These observations have led to question the relationship between the ontogeny, and the functions in KCs. To date, there are no phenotypic markers to exclusively identify an ontogenetically distinct subset, and this has hampered functional studies of this subset. In this dissertation, we explore how the embryo-derived KC subset in the liver respond to irradiation stress and to acute inflammatory stimuli. To this end, we developed a mouse model to specifically label the embryo-derived KCs in the adult liver and assessed their response to lethal irradiation. We found that the embryo-derived subset resists lethal irradiation and this resistance is mediated through the p21-cip1/WAF1 protein. In contrast, the same dose of radiation depleted the bone marrow monocyte-derived KCs. Together, these results indicate that the embryonic origin provides enhanced survival to radiation induced injury. In a lipopolysaccharide-mediated acute inflammation model, the embryo-derived subset responded readily mounting a pro-inflammatory gene expression pattern. Once the inflammatory stimuli subsided they revert back to the steady state gene expression pattern. These observations indicate that this embryo-derived subset retains plasticity and are able to respond to changing environmental cues. The research work in this dissertation provides first insights into the underlying biology of embryo-derived KCs. We explored how an embryo-derived KC subset responds to radiation induced sterile damage and to systemic acute inflammation. We demonstrate that in both these models, the embryonic subset possesses remarkable ability to resist damage, avoid depletion, respond to changing environment, and reset to steady state.