Tim-3 exacerbates kidney ischaemia/reperfusion injury through the TLR-4/NF-κB signalling pathway and an NLR-C4 inflammasome activation

Y Guo, J Zhang, X Lai, M Chen, Y Guo
Clinical and Experimental Immunology 2018, 193 (1): 113-129
T cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3), a member of the immunoglobulin superfamily, has been shown to play a crucial role in host adaptive immunity and tolerance. However, its role in kidney ischaemia-reperfusion injury (IRI) remains unknown. In this study, we investigated the role and mechanism of Tim-3 signalling after kidney IRI. In an established murine model of kidney IRI, we found that Tim-3 expression is enhanced on monocytes/macrophages. Anti-Tim-3 antibody RMT3-23 ameliorates biochemical and histological kidney injury, reduces apoptosis and decreases macrophage infiltration and cytokine production in ischaemic kidneys. Cell culture experiments also demonstrated that the role of Tim-3 in IRI-induced macrophage activation leads to the secretion of proinflammatory cytokines and chemokines. In addition, Toll-like receptor (TLR)-4 and Nod-like receptor (NLR) family CARD domain-containing protein 4 (NLR-C4) expression were enhanced after kidney IRI and decreased significantly by RMT3-23. Tim-3 not only promotes TLR-mediated nuclear factor kappa B (NF-κB) activation and cytokine and chemokine release, but also participates in NLR-C4 inflammasome activation. Taken together, our data confirm that Tim-3 signalling enhances injury after kidney IRI and demonstrated that Tim-3 is involved in regulating TLR-4/NF-κB signalling and NLR-C4 inflammasome activation, which provide evidence that Tim-3 signalling is critical for kidney IRI and may provide a new means to ameliorate kidney tissue immune responses in the clinics.

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