Sensing Dying Cells in Health and Disease: The Importance of Kidney Injury Molecule-1

Kidney Injury Molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain-1 (TIM-1), is a widely recognized biomarker for acute kidney injury, but its biological function is less appreciated. KIM-1/TIM-1 belongs to the TIM family of conserved transmembrane proteins which bear the characteristic six-cysteine immunoglobulin-like (IgV) domain. The latter enables binding of KIM-1/TIM-1 to its natural ligand, phosphatidylserine, expressed on the surface of apoptotic cells and necrotic cells. KIM-1/TIM-1 is expressed in a variety of tissues and plays fundamental roles in regulating sterile inflammation and adaptive immune responses. In the kidney, KIM-1 is upregulated on injured renal proximal tubule cells transforming them into phagocytes for clearance of dying cells and helps to dampen sterile inflammation. TIM-1 expressed in T cells, B cells, and Natural Killer T (NKT) cells, is essential for cell activation and immune regulatory functions in the host. Functional polymorphisms in the gene for KIM-1/TIM-1, HAVCR1, have been associated with susceptibility to immunoinflammatory conditions, and Hepatitis A virus-induced liver failure which is thought to be due to a differential ability of KIM-1/TIM-1 variants to bind phosphatidylserine. This review will summarize the role of KIM-1/TIM-1 in health and disease, and its potential clinical applications as a biomarker and therapeutic target in humans.