Transcriptomic atlas reveals organ-specific disease tolerance in sickle cell mice

Abstract

Abstract: Sickle cell disease (SCD) is the most common genetic disease in the world and a societal challenge. SCD is characterized by multiorgan injury related to intravascular hemolysis. To understand tissue-specific responses to intravascular hemolysis and exposure to heme, we present a transcriptomic atlas of the primary target organs of hemoglobin S (HbSS) vs hemoglobin 1 (HbAA) transgenic SCD mice. We explored the transcriptomes of the liver, kidney, heart, lung, and bone marrow from HbAA and HbSS Townes littermates at resting state and their changes after the injection of heme, assessed by RNA sequencing. Inflammation and myeloid cell signatures were omnipresent in resting HbSS organs, with the liver being the most affected. The injection of heme triggered a robust inflammatory response in HbAA mice. Signatures of exposure to heme in HbAA mice were downstream of toll like receptor 4, sensor of lipopolysaccharides but also of heme, interleukin-1β (IL-1β), IL-6, and interferon gamma, similarly to HbSS mice at rest. Nevertheless, HbSS mice were strikingly unresponsive to the heme administration, irrespective of the organ. This tolerance was driven by upregulation of the heme-detoxifying enzyme heme oxygenase-1 and was abrogated by its specific inhibition. Therefore, HbSS mice develop robust protective mechanisms, which may explain how they and patients with SCD survive bouts of severe hemolysis.