Targeted Inhibition of CD74+ Macrophages by Luteolin via CEBPB/P65 Signaling Ameliorates Osteoarthritis Progression
1Department of Bone and Joint Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Abstract:
Synovial inflammation represents a hallmark pathological process in osteoarthritis (OA), yet the cellular drivers orchestrating this response remain incompletely defined. Through single-cell transcriptomic profiling of human OA synovial tissues, a distinct subset of CD74⁺ macrophages is identified that displayed robust pro-inflammatory transcriptional signatures, underscoring the pivotal role of macrophages in shaping the inflammatory microenvironment. To explore therapeutic opportunities, computational ligand-target interaction analysis predicted luteolin as a high-affinity binder of CD74. Mechanistically, luteolin suppressed CD74 expression and disrupted the assembly of the CEBPB-p65 complex, thereby preventing p65 nuclear translocation and subsequent activation of the NF-κB signaling cascade in macrophages. To achieve targeted delivery, a nanoplatform MIF79-86-DS-PLGA-Luteolin (MDSPL) is engineered by conjugating MIF-mimetic peptides onto reactive oxygen species (ROS)-responsive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, enabling selective recognition of CD74⁺ macrophages. In vivo, MDSPL exhibited superior efficacy over free luteolin in attenuating synovial inflammation and halting OA progression. Notably, early intervention with MDSPL yielded stronger chondroprotective effects than delayed administration, highlighting the therapeutic value of timely targeting of macrophage-driven inflammation. Collectively, these findings establish CD74⁺ macrophages as a pathogenic driver of OA-associated synovial inflammation and introduce MDSPL as a precision nanotherapeutic strategy with translational potential for OA management.
Insights
Osteoarthritis (OA) involves synovial inflammation driven by CD74-positive macrophages. A novel nanotherapeutic, MDSPL, targets these macrophages, effectively reducing inflammation and halting OA progression for potential treatment.
Area of Science:
- Immunology
- Nanomedicine
- Molecular Biology
Background:
- Synovial inflammation is central to osteoarthritis (OA) pathogenesis.
- The specific immune cells driving OA synovial inflammation are not fully understood.
- Macrophages are implicated in OA inflammation, but their precise role requires further definition.
Purpose of the Study:
- To identify cellular drivers of synovial inflammation in osteoarthritis.
- To investigate luteolin as a potential therapeutic targeting CD74.
- To develop and evaluate a targeted nanodelivery system for OA treatment.
Main Methods:
- Single-cell transcriptomic profiling of human OA synovial tissues.
- Computational ligand-target interaction analysis.
- In vitro mechanistic studies on macrophage signaling pathways (NF-κB).
- Engineering of ROS-responsive nanoparticles (MDSPL) for targeted delivery.
- In vivo assessment of MDSPL efficacy in an OA model.
Main Results:
- A subset of CD74-positive macrophages with pro-inflammatory signatures was identified in OA synovium.
- Luteolin was predicted to bind CD74 and was shown to suppress NF-κB signaling in macrophages.
- The engineered MDSPL nanoparticles selectively targeted CD74-positive macrophages.
- MDSPL demonstrated superior efficacy in reducing synovial inflammation and halting OA progression compared to free luteolin.
- Early intervention with MDSPL showed enhanced chondroprotective effects.
Conclusions:
- CD74-positive macrophages are key drivers of synovial inflammation in osteoarthritis.
- MDSPL represents a precision nanotherapeutic strategy for OA management.
- Targeting macrophage-driven inflammation offers a promising therapeutic avenue for osteoarthritis.