Immunobiology of a novel human DAMP receptor, its murine homolog, & their ligand

Abstract The immune system has evolved mechanisms to recognize and respond to cell injury and this response contributes in important ways to both health and disease. In this process, alarm signals called Damage Associated Molecular Patterns (DAMPs) are released from injured cells and these are then detected by receptors on innate immune cells, which trigger sterile inflammation. These responses are thought to be important for host defense, but also cause tissue damage that contributes to a number of diseases. Because of this, it is important to identify the key DAMPs that drive these responses and also the receptors that engage these ligands and mediate their effects. While we and others have discovered a few DAMPs/DAMP receptors, it is clear that there are others yet to be discovered. Moreover, the DAMP/DAMP receptors have been primarily studied in mice and less is known about these in humans. This grant is based on our preliminary discoveries of a novel DAMP receptor in humans, Clec17a, a related murine counterpart, CD209f/g, and their novel DAMP ligand, GAPDH, which is highly conserved, broadly expressed, and abundant. These discoveries form the basis for this grant. Our central hypothesis is that Clec17a in humans and CD209f/g in mice are key receptors on innate immune cells that sense the release of GAPDH from injured cells and help drive the ensuing sterile inflammatory response and its associated pathology. We have 3 specific Aims to elucidate the structure and function of this novel DAMP and its receptors. Aim 1 will elucidate in humans what innate immune cells are stimulated by GAPDH, the nature and biology of their responses and the role of Clec17a in this process. In addition, this aim will seek to determine the specificity of this response and how it fits in with responses stimulated by other DAMPs. The importance of these goals is that they will establish a novel DAMP-DAMP receptor in humans, elucidate their pathophysiology, and provide insight into how humans recognize and respond to cell injury. Aim 2 will investigate the structural and functional murine counterpart of human Clec17a, and elucidate its role, and that of GAPDH, in mice. Aim 3 will elucidate the underlying molecular mechanisms by which human Clec17a and mouse CD209f/g trigger innate immune cells and ultimately drive host defense and pathobiology.