Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury

Abstract The immune system has evolved mechanisms to recognize cell injury and in response stimulate sterile inflammation. This response contributes in important ways to both heath and disease. In this process, dying cells release Damage Associated Cell Patterns (DAMPs) that are detected by receptors on immune cells, which then trigger sterile inflammation. Histones are DAMPs that are major drivers of sterile inflammation and there is a recent growing literature implicating the release of and response to histones in the morbidity and mortality from tissue injury. Given the role of these DAMPs in the pathogenesis of disease, it is important to understand the receptors that engage these ligands and mediate their effects. Before our work, such receptors were unknown. We discovered the first cellular receptor for histones, which was the C-type lectin receptor (CLR/Clec) Clec2d. We showed that Clec2d plays an important role in innate immune responses to histones and the pathogenesis of disease in vivo. Our studies also revealed that Clec2d is not the whole story and that there must be another histone receptor(s) in mice that contributes to responses and disease. Moreover, human innate immune cells are similarly stimulated by histones, however when we went to translate our findings to humans, we found that the human homolog of Clec2d does not recognize histones. Therefore, there are as yet to be identified human histone receptors. Importantly, we have now discovered such novel Clec-histone receptors (CHRs) in both mice and humans and these discoveries form the basis for this grant application. We have two Aims: Aim 1 will elucidate the role of CHRs in innate immune responses to histones in vivo. We will define what innate immune cells use CHRs to sense histones in vivo, the nature of the subsequent responses, and their role in the sterile inflammatory response and pathogenic sequelae of tissue injury in vivo. The importance of this aim is that it will provide insight into disease pathogenesis and potentially identify new molecular targets for treating these conditions; and, Aim 2 will define the specificity, consequences and underlying mechanisms of histone stimulation of novel CHRs. The importance of this aim is that it will define the underlying mechanisms by which histones and their receptors trigger and regulate responses, which ultimately drive host defense and pathobiology.