KIM-1/TIM-1 in proximal tubular cell immune response

Kidney injury molecule-1/T cell IgG and mucin containing 1 (KIM-1/TIM-1) is a type 1 membrane receptor [1] which we identified as the most upregulated proximal tubular cell (PTC) protein following a variety of kidney injuries in animal models and human diseases [1] (Figure 1A). While KIM-1 (also known as hepatitis A virus cellular receptor-1 (HAVCR-1)) quickly was recognized as a promising biomarker, other proteins were subsequently discovered which, together with KIM-1/ TIM-1 formed a new class of proteins (TIMs) whose function was unknown at the time of discovery. Work from our lab identified KIM-1’s function as an apoptotic cell phosphatidylserine phagocytosis and scavenger receptor [2], whereby it induces the binding and uptake of dead cells from the kidney tubule lumen in acute kidney injury (AKI) (Figure 1B). As is often the case, however, identifying the function of KIM-1 only led to more questions: Why do non-myeloid cells express a scavenger receptor? Can PTCs efficiently phagocytose in vivo? What are the functional consequences of PTC phagocytosis? In other words, what is the role of KIM-1 in kidney injury? To address these questions, we characterized a mouse model KIM-1Δmucin (in collaboration with Dr. Vijay Kuchroo’s lab), which expressed a truncated, phagocytosis deficient KIM-1 molecule, by deleting the mucin domain, (the domain where most mutations leading to human disease occur), while retaining most of the protein intact [3]. Utilizing this novel animal model, we found that KIM-1 mediated phagocytosis is responsible for the clearance of much of the luminal apoptotic cells resulting from ischemic or nephrotoxic acute tubular injury [4]. In addition, KIM-1 expression down-regulates PTC cytokine secretion, which is further down-regulated with the KIM-1-mediated uptake of apoptotic cells. Using a systems biology approach, we identified post-translational modifications to the NFκB pathway as the most likely pathway modulated by KIM-1 to regulate cytokine secretion [4]. Indeed, KIM-1 expression and phagocytosis decreases NFκB phosphorylation and activity. KIM-1 phosphorylation regulates the NFκB pathway through interaction and regulation of the PI3 kinase subunit p85. In the KIM-1Δmucin mice, decreased apoptotic cell clearance, increased pro-inflammatory cytokine secretion and increased immune cell infiltration culminated in more severe injury, when compared to wild-type mice, indicating intact KIM-1 plays a protective role in AKI [4]. In addition to acting as non-professional phagocytes, PTCs constitutively express MHC II and can activate naïve T cells; thus, PTCs are also semiprofessional antigen presenting cells [5]. To determine if KIM-1-mediated phagocytosis promotes presentation of phagocytosed antigens, we first examined the uptake and processing of apoptotic cells in vitro by adding apoptotic cells to the apical surface of cultured PTCs and monitoring phagocytosis (Figure 1C). Apoptotic cells taken up by KIM-1 are quickly targeted by LC3 in the cytosol. LC3 localization to KIM-1 phagosomes required the expression of autophagy factors ATG5, Beclin1 and ULK1 [6]. Mutation to the KIM-1 ligand-binding domain Editorial