Type II alveolar epithelial cell regulation of alveolar macrophage development, metabolism and immune function by a novel NKR-P1:Clr interaction.

People that suffer acute lung injury from infections or inhaling toxic substances often have ‘foamy’ macrophages in their lungs. During studies on natural killer cells, our laboratory observed that mice that are lacking the NKR-P1B protein are extremely susceptible to lung infections. We found that this is due to these mice having almost no alveolar macrophages in an age-dependent fashion. The reason for the lack of macrophages in the lung is that they normally express NKR-P1B on their surface and that this expression regulates their main function which is to ‘eat’ lung surfactant, a sticky substance that traps inhaled particulate matter including microbes. Without NKR-P1B, alveolar macrophages gobble up surfactant at a much increased rate leading to death of these cells by a process termed lipotoxicity. Furthermore, we discovered that this regulation by NKR-P1B is made possible through interaction with a second protein, the ‘ligand’ for NKRP1B, on lung epithelial cells. The ligand for NKR-P1B is called Clr-g, and is turned off on type II alveolar epithelial cells during viral or bacterial infections. This new receptor:ligand pair, and its regulation of alveolar macrophage immune responses and metabolism has not been described previously. In this grant application we request funds to answer the following questions: 1) What metabolic pathways are regulated by NKR-P1B:Clr-g interactions and how do they affect immune responses in the lung? 2) What are the molecular signals emanating from NKR-P1B on the surface of alveolar macrophages and which signal transduction pathways do they affect? 3) How do lung epithelial cells regulate Clr-g expression in order to control alveolar macrophage function? We believe answers to these questions will give us a better understanding of how alveolar macrophages are regulated day-to-day and during infections leading to better treatments for acute lung injuries.