Frontline Science: Tim-3-mediated dysfunctional engulfment of apoptotic cells in SLE

Abstract

T cell Ig and mucin domain-containing molecule 3 (Tim-3) has been found to play important roles in autoimmune diseases, but whether Tim-3-mediated engulfment of apoptotic cells is involved in systemic lupus erythematosus (SLE) remains to be elucidated. In this study, we verified the role of human Tim-3 (hTim-3) as the receptor of phosphatidylserine (PS) in human embryonic kidney (HEK)293 cells, which initiated the engulfment of apoptotic cells. Both IgV and the mucin domain of Tim-3 were crucial in the phagocytosis of apoptotic cells, and there existed the key cytoplasmic domain for signal transduction. Alanine at 111, locating around the FG-CC' loop of hTim-3, was necessary for its engulfment of apoptotic cells. In accordance, Tim-3 on CD14 cells negatively correlated with the percentage of peripheral apoptotic cells in control subjects. However, although Tim-3 was significantly increased on CD14 cells in SLE patients, peripheral apoptotic cells remained much higher than those in control subjects. Tim-3 on CD14 cells showed positive correlation with percentage of apoptotic cells and level of dsDNA, indicating the involvement of Tim-3 in SLE. Accordingly, soluble Tim-3 (sTim-3) was significantly increased in plasma of SLE patients, which might contribute to higher expression of a disintegrin and metalloproteinase (ADAM)-10. Pretreatment with both plasma from SLE patients and recombinant sTim-3 greatly inhibited hTim-3-initiated phagocytosis of apoptotic cells. Furthermore, anti-Tim-3 antibody depletion of plasma from SLE patients reversed the decreased phagocytosis of apoptotic cells. Collectively, our data suggest that sTim-3 might play inhibitory roles in impaired Tim-3-mediated clearance of apoptotic cells in SLE.

Editorial: Countering immune regulation: sTim-ulating SLE disease pathogenesis

“…1). Together with work by Gao and colleagues [4], these studies highlight the dual function of Tim-3 in regulating immunity via both an interaction with apoptotic bodies to mediate clearance and via interactions with galectin-9 (and potentially other ligands) to inhibit activation and induce death of autoreactive T and B cells, diminishing potentially damaging adaptive immune responses. Importantly, interference with normal function of the Tim-3 pathway via production of sTim-3 breaks down this regulation, contributing to immunopathogenesis.…”

“…In the current issue of JLB, Zhao et al [4] present data to support a role for Tim-3 in enhancing autoimmune pathogenesis. With the examination of Tim-3 in the context of SLE, the authors find that in addition to being up-regulated on CD14 + cells, Tim-3 expression was associated with higher levels of apoptotic bodies in the plasma of SLE patients.…”

“…However, it is unclear how these proteins are regulated in SLE. Gao and colleagues [4] found that ADAM10 expression was significantly up-regulated on the PBMCs of SLE patients compared with healthy control subjects, providing a mechanistic explanation for the increased levels of plasma sTim-3. Furthermore, ADAM10 and ADAM17 are involved in other inflammatory diseases.…”

“…sTim-3 is the ectodomain of the protein that is cleaved from the cell surface via matrix metalloproteinases, ADAM10 and ADAM17 [5]. Gao and colleagues [4] subsequently show that sTim-3 acts as a soluble decoy, preventing clearance of apoptotic bodies that might otherwise interact with membrane-bound Tim-3 to mediate phagocytosis. As Tim-3 binds to PS, sTim-3 could also potentially inhibit phagocytosis mediated by other PS receptor proteins (reviewed in Birge et al [3]).…”

“…1). First, as described by Gao and colleagues [4], it may act to inhibit clearance of damaging apoptotic bodies, effectively enhancing the development of autoantibodies that exacerbate disease. Second, it may act to neutralize galectin-9, present in the plasma of SLE patients, preventing regulation of Th1, Th17, Tc1, and B cell responses.…”