Apoptotic body-inspired nanotherapeutics efficiently attenuate osteoarthritis by targeting BRD4-regulated synovial macrophage polarization
Copyright © 2024 Elsevier Ltd. All rights reserved..
Bromodomain-containing protein 4 (BRD4) is the most well-studied BET protein that is important for the innate immune response. We recently revealed that targeting BRD4 triggers apoptosis in tumor-associated macrophages, but its role in synovial macrophages and joint inflammation is largely unknown. Herein, we demonstrated that BRD4 was highly expressed in the iNOS-positive M1 macrophages in the human and mouse osteoarthritis (OA) synovium, and conditional knockout of BRD4 in the myeloid lineage using Lyz2-cre; BRD4flox/flox mice significantly abolished anterior cruciate ligament transection (ACLT)-induced M1 macrophage accumulation and synovial inflammation. Accordingly, we successfully constructed apoptotic body-inspired phosphatidylserine-containing nanoliposomes (PSLs) loaded with the BRD4 inhibitor JQ1 to regulate inflammatory macrophages. JQ1-loaded PSLs (JQ1PSLs) exhibited a higher cellular uptake by macrophages than fibroblast-like synoviocytes (FLSs) in vitro and in vivo, as well as the reduction in proinflammatory M1 macrophage polarization. Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse".
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:306 |
|---|---|
| Enthalten in: |
Biomaterials - 306(2024) vom: 05. März, Seite 122483 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xu, Yi-Di [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 01.03.2024 Date Revised 01.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.biomaterials.2024.122483 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368202275 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368202275 | ||
| 003 | DE-627 | ||
| 005 | 20240301232504.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240209s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.biomaterials.2024.122483 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1313.xml |
| 035 | |a (DE-627)NLM368202275 | ||
| 035 | |a (NLM)38330742 | ||
| 035 | |a (PII)S0142-9612(24)00017-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xu, Yi-Di |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Apoptotic body-inspired nanotherapeutics efficiently attenuate osteoarthritis by targeting BRD4-regulated synovial macrophage polarization |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.03.2024 | ||
| 500 | |a Date Revised 01.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Bromodomain-containing protein 4 (BRD4) is the most well-studied BET protein that is important for the innate immune response. We recently revealed that targeting BRD4 triggers apoptosis in tumor-associated macrophages, but its role in synovial macrophages and joint inflammation is largely unknown. Herein, we demonstrated that BRD4 was highly expressed in the iNOS-positive M1 macrophages in the human and mouse osteoarthritis (OA) synovium, and conditional knockout of BRD4 in the myeloid lineage using Lyz2-cre; BRD4flox/flox mice significantly abolished anterior cruciate ligament transection (ACLT)-induced M1 macrophage accumulation and synovial inflammation. Accordingly, we successfully constructed apoptotic body-inspired phosphatidylserine-containing nanoliposomes (PSLs) loaded with the BRD4 inhibitor JQ1 to regulate inflammatory macrophages. JQ1-loaded PSLs (JQ1PSLs) exhibited a higher cellular uptake by macrophages than fibroblast-like synoviocytes (FLSs) in vitro and in vivo, as well as the reduction in proinflammatory M1 macrophage polarization. Intra-articular injections of JQ1@PSLs showed prolonged retention within the joint, and remarkably reduced synovial inflammation and joint pain via suppressing M1 polarization accompanied by reduced TRPA1 expression by targeted inhibition of BRD4 in the macrophages, thus attenuating cartilage degradation during OA development. The results show that BRD4-inhibiting JQ1@PSLs can targeted-modulate macrophage polarization, which opens a new avenue for efficient OA therapy via a "Trojan horse" | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptotic body | |
| 650 | 4 | |a BRD4 | |
| 650 | 4 | |a Bioinspired nanotherapeutics | |
| 650 | 4 | |a Osteoarthritis | |
| 650 | 4 | |a Synovial macrophage polarization | |
| 650 | 7 | |a BRD4 protein, human |2 NLM | |
| 650 | 7 | |a Bromodomain Containing Proteins |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Brd4 protein, mouse |2 NLM | |
| 700 | 1 | |a Liang, Xiang-Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhi-Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Zhao-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Shi-Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhen-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-He |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Fang-Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jia-Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Wen-Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Zha, Zhen-Gang |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Huan-Tian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biomaterials |d 1989 |g 306(2024) vom: 05. März, Seite 122483 |w (DE-627)NLM012732516 |x 1878-5905 |7 nnns |
| 773 | 1 | 8 | |g volume:306 |g year:2024 |g day:05 |g month:03 |g pages:122483 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.biomaterials.2024.122483 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 306 |j 2024 |b 05 |c 03 |h 122483 | ||