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

Abstract

Kidney injury molecule-1 (KIM-1), also known as T-cell Ig and mucin domain-1 (TIM-1), is a widely recognized biomarker for AKI, but its biological function is less appreciated. KIM-1/TIM-1 belongs to the T-cell Ig and mucin domain family of conserved transmembrane proteins, which bear the characteristic six-cysteine Ig-like variable 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, which transforms 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 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.

Figure 1

KIM-1 signaling pathways in renal proximal tubule cells. ^aAnti-inflammatory pathway^,: KIM-1 binding to PS on apoptotic cells leads to recruitment of the p85 subunit of the PI3K and subsequent PI3K-dependent downregulation of NF-κB activation by TNFR and TLR4. LPS and TNF-α are known TLR4 and TNFR ligands, respectively. AIM is an opsonin that enhances the phagocytic clearance of necrotic cells by KIM-1 and thereby reduces necroinflammation.^{, b}Autophagy: phosphorylation of the cytosolic domain of KIM-1 and subsequent engagement of p85 enables activation of ULK1, which are necessary for localization of LC3, the phagosome, and lipidation of LC3 I to LC3 II (a hallmark of autophagy). KIM-1–positive phagosomes then fuse with the lysosome, and antigens derived from apoptotic cells are presented on class I and II MHC molecules. ^cCell survival^,: the nuclear orphan receptor NUR77 is a potent inducer of apoptosis. KIM-1 constitutively binds to NUR77 via its cytosolic tail and mediates its lysosomal degradation in a PI3K-dependent manner. ^dEfferocytosis^,,: coordinated rearrangement of the actin (F-actin polymerization) and microtubule cytoskeleton is crucial for engulfment of apoptotic cells. KIM-1–mediated inhibition of the Gα₁₂-RhoA axis and engagement of the dynein light chain Tctex-1 are required for efficient efferocytosis.^, RhoA can impair corpse ingestion by promoting actin stress fibers. ^eDisruption of tight junctions: overactivation of Gα₁₂ by ROS can disrupt tight junctions and promote tubular cell injury. ^fKIM-1 binding to DR5 promotes its multimerization and downstream caspase activation, leading to apoptosis of tubular cells. AC, apoptotic cell; AIM, apoptosis inhibitor of macrophage; DR5, death receptor 5; KIM-1, kidney injury molecule-1; MHC, major histocompatibility complex; NC, necrotic cell; NF-κB, nuclear factor-kappa B; PI3K, phosphoinositide 3-kinase; PS, phosphatidylserine; RhoA, ras homolog family member A; ROS, reactive oxygen species; Tctex-1, Tctex-type 1; TLR4, toll-like receptor 4; TNFR, TNF receptor; ULK1, Unc-51-like kinase. Created with BioRender.com.

Figure 2

The multifaceted role of TIM-1 in the immune system. (A) The role of TIM-1 T-cell responses in immunity and tolerance was largely based on studies whereby cell surface TIM-1 was ligated using activating (high-affinity 3B3) or inhibitory (low-affinity RMT1-0) anti–TIM-1 antibodies.^, The effect of TIM-1 engagement on T-cell responses seems to be dependent on the affinity and/or avidity of the corresponding antibody. For instance, 3B3 can costimulate CD4⁺ T-cell activation in vitro and block the development of tolerance when administered in vivo in mice.^, Thereby, 3B3 can promote airway inflammation and EAE, in mouse models of asthma and multiple sclerosis, especially.^, In transplant models, 3B3 inhibited allograft tolerance by promoting the expansion of Th1 and Th17 cells and deprogramming of Tregs cells. By contrast, RTM1-10 reduces antigen-specific CD4⁺ T (Th1 and Th17) responses, promotes Th2 responses, and prolongs the survival of heart allografts in vivo.^, TIM-1 also binds to P-selectin and mediates the trafficking of Th1 and Th2 cells during inflammation and autoimmune disease. (B) TIM-1 signaling is required for B regulatory cell (Breg) induction and maintenance and is an inclusive marker for IL-10–positive Bregs.^– In addition, TIM-1 ligation with RTM1–10 induces expansion of Bregs that express many checkpoint receptors (e.g., TIGIT) and produce IL-10.^,, TIM-1⁺ Bregs are required for maintenance of tolerance—mice that express TIM-1 lacking the mucin domain (TIM-1^Δmucin) or lacking TIM-1⁺ B cells develop age-related autoimmunity and harbor hyperactive T cells.^,,, Accordingly, treatment with RMT1-10 or adoptive transfer of TIM-1⁺ Bregs can prolong islet and heart allografts, respectively.^, TIM-1 reduces type 1 interferon responses in B cells, which in turn impacts B cell activation and inhibits antigen presentation and costimulation. (C) NKT cells constitutively express TIM-1 and can be activated via stimulation with 3B3 (but not RMT1-10) or apoptotic cells.^– Activated NKT cells can contribute to lung inflammation and liver injury in experimental models. CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; EAE, experimental autoimmune encephalomyelitis; IFN‐γ, interferon gamma; Il-4, interleukin 4; Il-10, interleukin 10; Il-13, interleukin 13; iNKT, invariant NKT cells; NKT, natural killer T; Th1, T-helper 1; Th2, T-helper 2; Th17, T-helper 17; TIGIT, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; TIM-1, T-cell Ig and mucin domain-1; TNF-α, tumor necrosis factor alpha; Treg, T regulatory. Created with BioRender.com.