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.
