Toll-like receptors in kidney ischemia-reperfusion injury: Modulating macrophage responses for therapeutic insights

Abstract

Kidney ischemia-reperfusion (I/R) injury is an acute clinical condition associated with inflammation and tissue damage during and after ischemia and reperfusion periods. In I/R injury, macrophages contribute to injury, and a family of proteins called toll-like receptors seem to have an immune modulatory role. When activated, TLRs initiate a series of signaling pathways, including MyD88 and TRIF. These pathways regulate the activation of tissue macrophages into either ‘classically activated’ M1 or ‘alternatively activated’ M2 phenotypes. Indeed, the relative abundance of these macrophage phenotypes defines the tissue injury level, which consequently requires reparative processes. The initial effector pro-inflammatory M1 macrophages aggravate tissue injury. Conversely, tissue reparative and anti-inflammatory M2 macrophages promote tissue repair and resolution—increased TLR signalling results in increased inflammation, prolonged healing and even renal failure. New evidence indicates that the change of macrophage responses through pharmacological targeting of the TLR pathways that regulate inflammation and tissue repair may have therapeutic implications. Some experimental treatment methods, in which early phases have been elaborated through experimental animal models, are TLR antagonists, small molecule inhibitors and nanotechnology-based delivery systems for Antisense oligonucleotide. Nevertheless, because the pathways regulated by TLRs and the subsets of macrophages are so countless and entangled, more extensive study is needed to provide more targeted actions. These findings shed light on the role and regulation of TLRs in macrophages during kidney I/R injury and investigate potential treatments with the potential to enhance care in this highly damaging condition.