Metabolic Characterization of Natural Killer T Cell responses to sterile, hypoxic injury (360G-Wellcome-210842_Z_18_Z)

It has been described that ischemia-reperfusion injury (IRI), such as during organ transplantation, evokes damaging sterile inflammation and secondary tissue injury that is dependent on iNKT cell activation, but the underlying mechanisms remain elusive. Similarly, in sickle cell disease (SCD) mice, RBC sickling and widely disseminated microvascular ischemia can be triggered by hypoxia/reperfusion (H/R), presenting a global and scalable model of sterile, NKT-mediated inflammation. We propose here to use state-of-the-art metabolic methodologies to investigate the response to hypoxia and reperfusion (H/R), which ultimately causes NKT cell activation and tissue damage in SCD. Mice carrying the human sickle cell alleles are available and were crossed with NKT-deficient Ja18 mice, thus generating our novel Sickle-Ja18 mouse model which exhibits reduced tissue damage in response to H/R. Together with in-vitro co-culture experiments, we will explore (1) the intrinsic and (2) APC-mediated mechanisms of sterile inflammation caused by hypoxia and reperfusion in the context of sickle cell disease with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis. We anticipate that this research will increase our understanding not only of SCD, but also the pathology of IRI, organ transplantation and sterile inflammation.