Abstract
The enhanced receptor activator of nuclear factor-κB (NFκB) ligand (RANKL) and its receptor (RANK) signal have been reported to attenuate ischemic brain injury through inhibition of Toll-like receptor (TLR) 4-mediated inflammation. However, augmentation of the RANKL/RANK signal also accelerates osteoporosis, which is a potential problem in clinical use of RANKL. Therefore, we developed novel peptides, microglial healing peptides (MHPs), which were based on the DE and/or EF loop of RANKL. Among them, MHP1 was the most effective inhibitor of TLR4-induced inflammations in microglia/macrophages. The effects depended on RANK, as confirmed by knockdown experiments. In contrast to RANKL, MHP1 did not stimulate osteoclast differentiation. Unexpectedly, MHP1 inhibited RANKL-induced osteoclast differentiation. These findings suggested that MHP1 was a partial agonist of RANKL, and administration of MHP1 attenuated ischemic injury by decreasing inflammation. MHP1 could be a novel therapeutic agent for treating ischemic stroke.
Highlights
Regulation of post-ischemic inflammation is an important strategy for treating ischemic stroke[1]
We have recently found that the receptor activator of nuclear factor-kB (NFκB) ligand (RANKL)/receptor activator of nuclear factor-κB (NFκB) (RANK) is a novel signal involved in the regulation of microglial inflammation through Toll-like receptor (TLR) 46, which is a main damage-associated molecular pattern (DAMP) receptor in the ischemic brain[1]
Because TLR2 is another important receptor for DAMPs in the ischemic brain[1] and other studies have shown that RANKL inhibited the TLR2 signal[12,13], we further investigated whether MHP1 could inhibit TLR2-stimulated signalling in MG6 cells
Summary
Regulation of post-ischemic inflammation is an important strategy for treating ischemic stroke[1]. Novel signalling processes that control post-ischemic inflammation have been explored to develop new therapeutic approaches Among these approaches, we have recently found that the receptor activator of nuclear factor-kB (NFκB) ligand (RANKL)/receptor activator of NFκB (RANK) is a novel signal involved in the regulation of microglial inflammation through Toll-like receptor (TLR) 46, which is a main damage-associated molecular pattern (DAMP) receptor in the ischemic brain[1]. We have recently found that the receptor activator of nuclear factor-kB (NFκB) ligand (RANKL)/receptor activator of NFκB (RANK) is a novel signal involved in the regulation of microglial inflammation through Toll-like receptor (TLR) 46, which is a main damage-associated molecular pattern (DAMP) receptor in the ischemic brain[1] Both RANKL and RANK are expressed in activated microglia and macrophages (M/M) of ischemic brain tissue, and enhancement of the RANKL/RANK signal using recombinant RANKL (rRANKL) has been shown to reduce ischemic injury in mice[6]; this indicated that rRANKL could potentially be used as a therapeutic agent for treating ischemic stroke. We examined the effects of MHP in the ischemic stroke model in mice to assess the potential of the peptide for treating ischemic stroke
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