Prevention of Acute Lung Injury by a Novel CD14-Inhibitory Receptor Activator of the NF-κB Ligand Peptide in Mice

Ju, Nan; Hayashi, Hiroki; Shimamura, Munehisa; Yoshida, Shota; Nakamaru, Ryo; Nakagami, Hironori; Morishita, Ryuichi; Rakugi, Hiromi

doi:10.4049/immunohorizons.2000112

Cited by 5 publications

(4 citation statements)

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“…companies' focus areas. Specifically, we have shown the efficacy of MHP1 in psoriasis 21) (in which TLR7 and TLR8 are involved in the pathogenesis of psoriasis), lung fibrosis, and acute lung injury models 19) (in which TLR2, TLR4, and TLR9 are related to the pathogenesis of these lung-related disorders). Through these experiments, we expanded the scope of therapeutic applications of MHP1 and elucidated the mechanism by which MHP1 suppresses TLR signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Some degraded products contain active moieties with antiinflammatory effects 18) , suggesting that the degraded peptides may have anti-inflammatory effects. Subsequent studies have revealed that MHP1 also acts on CD14, a TLR co-receptor, and inhibits the binding of TLR2, 4, 7, and 9 ligands to TLRs, thereby suppressing the expression of multiple proinflammatory cytokines 19) (Figure 2). In a mouse model of transient middle cerebral artery occlusion, MHP1 infiltrated only the infarcted area after intravenous infusion, and continuous subcutaneous infusion improved neurological symptoms for up to 8 h after the onset of ischemic stroke.…”

Section: Development Of Rankl Partial Peptide Mhp1 (Microglial Healin...mentioning

confidence: 99%

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Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Shimamura,

Nakagami,

Katsuya

et al. 2023

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Although post-ischemic stroke process is essential for the repair of the infarcted area, excessive inflammation during this process can induce tissue damage. Damage-associated molecular patterns (DAMPs) released from injured cells in the early phase of ischemic stroke induce cytokine and chemokine production by activating microglia, thereby facilitating neutrophil and lymphocyte infiltration. However, the inhibition of neutrophils, lymphocytes, and their associated proinflammatory molecules has shown no apparent improvement in the functional outcomes and prognosis of post-ischemic stroke. Therefore, the selection of molecules and cell types that regulate cytokine production is important. Considering that the increase and infiltration of activated microglia/macrophages (M/M) is the major pathological change in ischemic stroke in humans and that DAMP/toll-like receptor (TLR) signaling is the starting point for microglial activation, the regulation of TLR signaling in M/M may be an important therapeutic strategy in the management of ischemic stroke.We found that receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK) signaling, expressed in activated M/Ms, inhibited DAMPs and TLR4 signaling. We also developed a partial peptide of RANKL, named microglial healing peptide 1 (MHP1), which regulates multiple TLR signaling pathways via RANK and CD14. This peptide was effective in mouse and monkey models and could be used in combination with tissue plasminogen activators in humans. Currently, we are attempting to improve the stability and efficacy of these peptides.Drug discovery in the field of acute ischemic stroke remains challenging. Continued research on the molecular mechanisms and development of novel drugs is important for the development of drugs intended for patients with ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Section: Development Of Rankl Partial Peptide Mhp1 (Microglial Healin...mentioning

confidence: 99%

Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Shimamura,

Nakagami,

Katsuya

et al. 2023

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“…Injection of recombinant human CD14 in lean and obese mice has also been found to result in sepsis independent changes in adipose cell expression of metabolic genes. Interestingly, CD14 ‐deficient mice subjected to high‐fat diet are more resistant to obesity, insulin resistance and cardiovascular disease [65]. Subsequently, CD14 has been shown to regulate SIRT1 activity, a master regulator of metabolism [66].…”

Section: Cd14 In Human Diseasesmentioning

confidence: 99%

Role of CD14 in human disease

et al. 2023

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The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and tissue injury in macrophages and monocytes. However, roles for CD14 are increasingly being uncovered in disease responses in epithelial and endothelial cells. Consistent with these broader functions, CD14 expression is altered in a variety of non-immune cell types in response to a several of disease states. Moreover, soluble CD14 activated by factors from both pathogens and tissue damage may initiate signalling in a variety of non-immune cells. This review examined the current understanding CD14 in innate immunity as well as its potential functions in nonimmune cells and associated human diseases.

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“…Western blotting and immunostaining were performed, as described previously. 16 See the Supplemental Material for details.…”

Section: Western Blottingmentioning

confidence: 99%

R-spondin 3/LGR4 (Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4) Axis Is a Novel Inflammatory and Neurite Outgrowth Signaling System in the Ischemic Brain in Mice

Shimamura

Hayashi

et al. 2023

Stroke

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BACKGROUND: Although stimulation of Wnt/β-catenin signaling is an important strategy to treat ischemic stroke, its signaling pathway has not been fully clarified yet. Recently, RSPO3 (R-spondin 3)/LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4) signaling has resolved TLR4 (toll-like receptor 4)-induced inflammation in lung injury; however, whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of RSPO3/LGR4 signaling in the ischemic brain. METHODS: BALB/c mice were exposed to permanent distal middle cerebral artery and common carotid artery occlusion. Temporal RSPO3 and LGR4 expressions were examined, and the mice were randomly assigned to receive vehicle or recombinant RSPO3. The underlying mechanisms were investigated using microglial cell lines and primary mixed glia-endothelia-neuron and primary neuronal cultures. RESULTS: In the ischemic brain, RSPO3 and LGR4 were expressed in endothelial cells and microglia/macrophages and neurons, respectively. Stimulation of RSPO3/LGR4 signaling by recombinant RSPO3 recovered neurological deficits with decreased Il1β and iNOS mRNA on day 3 and increased Gap43 on day 9. In cultured cells, LGR4 was expressed in neuron and microglia, whereas RSPO3 promoted nuclear translocation of β-catenin. Neuroprotective effects with reduced expression of inflammatory cytokines were observed in lipopolysaccharide-stimulated glia-endothelium-neuron cultures but not in glutamate-, CoCl 2 -, H 2 O 2 -, or oxygen glucose deprivation-stimulated neuronal cultures, indicating that RSPO3/LGR4 can protect neurons by regulating inflammatory cytokines. LGR4-Fc chimera, which was used to block endogenous RSPO3/LGR4 signaling, increased LPS-induced production of inflammatory cytokines, suggesting that endogenous RSPO3 suppresses inflammation. RSPO3 decreased TLR4-related inflammatory cytokine expression by decreasing TLR4 expression without affecting the M1/M2 phenotype. RSPO3 also inhibited TLR2- and TLR9-induced inflammation but not TLR7-induced inflammation, and promoted neurite outgrowth. CONCLUSIONS: RSPO3/LGR4 signaling plays a critical role in regulating TLR-induced inflammation and neurite outgrowth in the ischemic brain. Enhancing this signal will be a promising approach for treating ischemic stroke.

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Prevention of Acute Lung Injury by a Novel CD14-Inhibitory Receptor Activator of the NF-κB Ligand Peptide in Mice

Cited by 5 publications

References 52 publications

Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Role of CD14 in human disease

R-spondin 3/LGR4 (Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4) Axis Is a Novel Inflammatory and Neurite Outgrowth Signaling System in the Ischemic Brain in Mice

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