The efficiency of the immune system to recognize and eliminate infected and tumor cells relies on its ability to detect danger signals and initiate inflammatory responses that will promote adaptive immunity. Incapacity to resolve the inflammation once the danger has been eliminated can lead to inflammatory disorders and has been recently implicated in promoting cancer. Yet, the cellular and molecular regulatory pathways involved in pro-inflammatory responses are poorly understood and the series of events occurring in situ remain to be elucidated. Our studies are focusing on the regulatory functions of activating NK receptors. The generation of genetically modified mice deficient for NKG2D and NKp46 will be instrumental to investigate the scope of NK-receptors s role in pathologies associated to chronic inflammation such as autoimmune disorders and inflammation-related cancer. We will use models of disease that mimic human pathologies to address the interplay between the inflammatory milieu and the NK-receptors in situ and to understand which cell interactions and/or mediators enhance tumor progression by contributing to sustained inflammation.